Thermal Treatment Of An Implantable Medical Device

ABSTRACT

A method of manufacturing an implantable medical device, such as a drug eluting stent, is disclosed. The method includes subjecting an implantable medical device that includes a polymer to a thermal condition. The thermal condition can result in reduction of the rate of release of an active agent from the device subsequent to the implantation of the device and/or improve the mechanical properties of a polymeric coating on the device.

CROSS-REFERENCE

This application is a divisional application of U.S. patent applicationSer. No. 10/856,984, filed on May 27, 2004 and published on Oct. 20,2005 as U.S. patent application publication number US 2005-0233062 A1,and which is incorporated by reference as if fully set forth, includingany drawings, herein. U.S. patent application Ser. No. 10/856,984 is acontinuation-in-part of U.S. patent application Ser. No. 10/603,794,filed on Jun. 25, 2003, and which issued as U.S. Pat. No. 7,682,647 onMar. 23, 2010. U.S. patent application Ser. No. 10/603,794 and U.S.patent application Ser. No. 10/856,984 are also continuation-in-parts ofU.S. patent application Ser. No. 10/108,004, which was filed on Mar. 27,2002. Furthermore, U.S. patent application Ser. No. 10/603,794 and U.S.patent application Ser. No. 10/856,984 are continuation-in-parts of U.S.patent application Ser. No. 10/304,360, now abandoned, filed on Nov. 25,2002, which is a divisional application of U.S. patent application Ser.No. 09/751,691, filed on Dec. 28, 2000, and which issued as U.S. Pat.No. 6,503,556 on Jan. 7, 2003. Additionally, U.S. patent applicationSer. No. 10/856,984 is a continuation-in-part of U.S. patent applicationSer. No. 10/751,043, now abandoned, filed on Jan. 2, 2004. U.S. patentapplication Ser. No. 10/603,794 is a continuation-in-part of U.S. patentapplication Ser. No. 09/750,595, and U.S. patent application Ser. No.10/751,043 is a continuation of U.S. patent application Ser. No.09/750,595, filed on Dec. 28, 2000, and which issued as U.S. Pat. No.6,790,228 on Sep. 14, 2004. U.S. patent application Ser. No. 09/750,595is a continuation-in-part of U.S. patent application Ser. No.09/470,559, filed on Dec. 23, 1999, which issued as U.S. Pat. No.6,713,119 on Mar. 30, 2004. U.S. patent application Ser. No. 09/470,559is a continuation-in-part of U.S. patent application Ser. No.09/390,855, filed on Sep. 3, 1999 and issuing as U.S. Pat. No. 6,287,628on Sep. 11, 2001, and U.S. patent application Ser. No. 09/470,559 isalso a continuation-in-part of U.S. patent application Ser. No.09/390,069, filed on Sep. 3, 1999 and issuing as U.S. Pat. No. 6,379,381on Apr. 30, 2002. U.S. patent application Ser. No. 09/750,595 is also acontinuation-in-part of U.S. patent application Ser. No. 09/715,510,filed on Nov. 17, 2000 and issuing as U.S. Pat. No. 6,749,626 on Jun.15, 2004, which is a continuation-in-part of U.S. patent applicationSer. No. 09/540,241, now abandoned, filed on Mar. 31, 2000.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The invention relates to implantable medical devices, one example ofwhich is a stent. More particularly, the invention relates to a methodof thermally treating an implantable medical device that includes apolymer, for example, a polymeric coating on the device.

2. Description of the Background

Percutaneous transluminal coronary angioplasty (PTCA) is a procedure fortreating heart disease. A catheter assembly having a balloon portion isintroduced percutaneously into the cardiovascular system of a patientvia the brachial or femoral artery. The catheter assembly is advancedthrough the coronary vasculature until the balloon portion is positionedacross the occlusive lesion. Once in position across the lesion, theballoon is inflated to a predetermined size to remodel the vessel wall.The balloon is then deflated to a smaller profile to allow the catheterto be withdrawn from the patient's vasculature.

A problem associated with the above procedure includes formation ofintimal flaps or torn arterial linings, which can collapse and occludethe conduit after the balloon is deflated. Vasospasms and recoil of thevessel wall also threaten vessel closure. Moreover, thrombosis andrestenosis of the artery may develop over several months after theprocedure, which may necessitate another angioplasty procedure or asurgical by-pass operation. To reduce the partial or total occlusion ofthe artery by the collapse of arterial lining and to reduce the chanceof the development of thrombosis and restenosis, a stent is implanted inthe lumen to maintain the vascular patency.

Stents act as scaffoldings, functioning to physically hold open and, ifdesired, to expand the wall of the passageway. Typically, stents arecapable of being compressed so that they can be inserted through smalllumens via catheters and then expanded to a larger diameter once theyare at the desired location. Mechanical intervention via stents hasreduced the rate of restenosis as compared to balloon angioplasty. Yet,restenosis is still a significant clinical problem with rates rangingfrom 20-40%. When restenosis does occur in the stented segment, itstreatment can be challenging, as clinical options are more limited ascompared to lesions that were treated solely with a balloon.

Stents are used not only for mechanical intervention but also asvehicles for providing biological therapy. Biological therapy can beachieved by medicating the stents. Medicated stents provide for thelocal administration of a therapeutic substance at the diseased site. Inorder to provide an efficacious concentration to the treated site,systemic administration of such medication often produces adverse oreven toxic side effects for the patient. Local delivery is a preferredmethod of treatment in that smaller total levels of medication areadministered in comparison to systemic dosages, but are concentrated ata specific site. Local delivery thus produces fewer side effects andachieves more favorable results.

One proposed method of medicating stents involves the use of a polymericcarrier coated onto the surface of the stent. A composition including asolvent, a polymer dissolved in the solvent, and an active agentdispersed in the blend is applied to the stent by immersing the stent inthe composition or by spraying the composition onto the stent. Thesolvent is allowed to evaporate, leaving on the stent strut surfaces acoating of the polymer and the active agent impregnated in the polymer.

A stent coating can be exposed to significant stress, for example,radial expansion as the stent is deployed. A potential shortcoming ofthe foregoing method of medicating stents is that the mechanicalintegrity of a polymeric drug coating can fail in the biological lumen,for example as a result of stress. In some instances, the polymericcoating may have poor adhesion to the surface of the stent. In otherinstances, if the polymeric coating contains multiple layers ofmaterials, the different layers may not attach well to each other andlack sufficient cohesiveness. Poor cohesion can result if there isinadequate interfacial compatibility between the surface of the stentand the polymer in the coating.

Failure of the mechanical integrity of the polymeric coating while thestent is localized in a patient can lead to a serious risk ofembolization because a piece of the polymeric coating can tear or breakoff from the stent. Polymeric stent coatings having a high drug loadingare especially vulnerable to fracture during and after deployment.

It is desirable to provide a polymeric coating that has improvedadhesion to the surface of the stent. It also is desirable to improvethe cohesion of multiple layers of polymeric material on a stent.Moreover, it is desirable to be able to increase the quantity of thetherapeutic substance carried by the polymeric coating withoutperturbing the mechanical properties of the coating or significantlyincreasing the thickness of the coating.

Another potential shortcoming of the foregoing method of medicatingstents is that the release rate of the active agent may be too high toprovide an efficacious treatment. This shortcoming may be especiallypronounced with certain active agents. For instance, it has been foundthat the release rate of 40-O-(2-hydroxy)ethyl-rapamycin from a standardpolymeric coating is greater than 50% in about 24 hours. Thus, there isa need for a coating that reduces the release rate of active agents inorder to provide a more efficacious release rate profile.

Yet another shortcoming is that there can be significant manufacturinginconsistencies. For instance, there can be release rate variabilityamong different stents. It is believed that when some polymers dry on astent surface to form a coating, different polymer morphologies candevelop for different stent coatings, even if the coating processparameters are consistent. The differences in polymer morphology maycause the release rate of the active agent from the polymeric coatingsto vary significantly. As a consequence of the inconsistent release rateprofiles among stents, there can be clinical complications.Additionally, when stents are stored, the release rate from the stentcoating can change during the storage time, known as “release ratedrift.” Thus, there is a need for a method that reduces the variabilityof the release rate of active agents among stents and over time.

The present invention provides a method and coating to meet theforegoing as well as other needs.

SUMMARY

According to one aspect of the present invention, a method of coating animplantable medical device is disclosed, the method including applying acomposition to an implantable medical device, the composition includinga polymer component and a solvent; and heating the polymer component toa temperature equal to or greater than the glass transition temperatureof the polymer component. In one embodiment, the temperature is (a)equal to the glass transition temperature of the polymer component plusthe melting temperature of the polymer component, divided by 2; (b)equal to 0.9 times the melting temperature of the polymer component,wherein the melting temperature of the polymer component is expressed inKelvin; (c) less than the melting temperature of the polymer component;(d) greater than the melting temperature of the polymer component; or(e) equal to or greater than the crystallization temperature of thepolymer component. In another embodiment, the polymer component isheated at a temperature equal to or greater than the glass transitiontemperature until a dry coating is formed on the device and optionallyfor a period of time thereafter, the dry coating comprising (a) lessthan about 10% residual solvent or water (w/w); (b) less than about 2%residual solvent or water (w/w); (c) less than about 1% residual solventor water (w/w); or (d) 0% residual solvent or water (w/w). In oneembodiment, the composition is free of any active agents, while inanother embodiment, the composition further includes an active agent.

According to another aspect, a method of manufacturing an implantablemedical device is disclosed, the method including applying asemicrystalline polymer to an implantable medical device; and exposingthe polymer to a temperature equal to or greater than thecrystallization temperature of the polymer for a duration of time. Inone embodiment, the polymer includes poly(lactic acid). In anotherembodiment, the polymer includes a block copolymer or a graft copolymer,wherein a moiety of the block copolymer or the graft copolymer ispoly(lactic acid).

In another aspect, a method of manufacturing a stent having a body madeat least in part from a polymer component is disclosed, the methodcomprising exposing the polymer component to a temperature equal to orgreater than the glass transition temperature of the polymer component.In one embodiment, the stent is a biodegradable stent.

According to a further aspect, a method of manufacturing an implantablemedical device is disclosed, the method including forming a first regionincluding a first polymer on the device; forming a second region of asecond polymer on the device, the second region including an activeagent, the first region being over or under the second region; andheating (i) the first polymer to a temperature equal to or above theglass transition temperature of the first polymer, or (ii) the secondpolymer to a temperature equal to or above the glass transitiontemperature of the second polymer. In one embodiment, the first polymerhas a glass transition temperature greater than the second polymer. Inanother embodiment, the second polymer has a glass transitiontemperature greater than the first polymer.

In yet another aspect, a method of manufacturing a stent coating isdisclosed, the method including applying a composition to a stent, thecomposition including a polymer and a solvent; allowing some, most orall of the solvent to evaporate to form a coating; and exposing thecoating to a temperature sufficient to increase the crystallinity of thepolymer in at least a portion of the coating.

In a further aspect of the present invention, a method of manufacturingan implantable medical device is disclosed, the device including apolymer and a drug, where the method comprises treating the device to atemperature greater than ambient temperature for a duration of time,wherein the temperature and the duration of exposure are sufficient todecrease the release rate of the drug from the device after the devicehas been implanted into a biological lumen. In one embodiment, thedevice is made in whole or in part from the polymer. In anotherembodiment, the polymer is biodegradable. In yet another embodiment, thestandard deviation of the mean release rate of the drug in a 24 hourperiod is lower than the standard deviation of the mean release rate fora group of devices which have not been exposed to the temperature.

In yet another aspect, a method of manufacturing a coating for animplantable medical device is disclosed, the method including exposing apolymeric coating on the device to a temperature greater than ambienttemperature for a duration of time, wherein the temperature and theduration of exposure is sufficient to increase the adhesion of thepolymeric coating to the device. In one embodiment, the polymericcoating is free from any active agents. In another embodiment, thepolymeric coating includes an amorphous polymer. In yet anotherembodiment, the polymeric coating includes a bioabsorable polymer.

In a further aspect of the present invention, a method of forming acoating for an implantable medical device is disclosed, the methodincluding (a) applying a first composition including a first polymer anda solvent on the device; (b) heating the first polymer to a temperatureequal to or greater than about the glass transition temperature of thefirst polymer; (c) applying a second composition including a secondpolymer and a solvent over the first polymer; and (d) heating the secondpolymer to a temperature equal to or greater than about the glasstransition temperature of the second polymer. In one embodiment, theheating of the first polymer is conducted after removal of some, most orall of the solvent in the first composition. In another embodiment, theheating of the second polymer is conducted after removal of some, mostor all of the solvent in the second composition. In yet anotherembodiment, the first or the second composition, but not both,additionally include an active agent.

BRIEF DESCRIPTION OF THE FIGURES

FIGS. 1A-1H illustrate coatings deposited on an implantable medicalsubstrate in accordance with various embodiments of the presentinvention;

FIG. 2 is an illustration of a system for thermally treating stents;

FIG. 3 is a graph of the relationship of heat capacity versustemperature for a polymer;

FIG. 4 is graph of the relationship of elasticity versus temperature fora polymer;

FIG. 5 is a graph of the relationship of specific volume versustemperature for a polymer;

FIG. 6A illustrates a fluid on a solid substrate having a contact angleΦ₁;

FIG. 6B illustrates a fluid on a solid substrate having a contact angleΦ₂;

FIG. 7 graphically illustrates elution profiles for stents with acoating of ethylene vinyl alcohol copolymer impregnated with vinblastinemade according to Example 4;

FIG. 8 graphically illustrates in vitro experimental data, in accordancewith Example 15, showing affects of actinomycin D, mitomycin, anddocetaxel on smooth muscle cell proliferation;

FIG. 9A is a picture of a histology slide of a coronary vessel from thecontrol group in accordance with Example 16;

FIG. 9B is a picture of a histology slide of a coronary vessel from theactinomycin D group in accordance with Example 16;

FIG. 10A is a picture of a histology slide of a coronary vessel from thecontrol group in accordance with Example 26;

FIG. 10B is a picture of a histology slide of a coronary vessel from theactinomycin D group in accordance with Example 26;

FIG. 11 is a graph showing the release rate of an active agent fromstent coatings as referred to in Example 42;

FIG. 12 is a graph showing the release rate of an active agent fromstent coatings as referred to in Example 53;

FIG. 13 is a chromatograph as referred to in Examples 68 and 69;

FIG. 14 is a graph showing the release rate of an active agent fromstent coatings as referred to in Example 72;

FIGS. 15-19 are photographs as referred to in Example 103; and

FIGS. 20-24 are graphs as referred to in Example 109.

DETAILED DESCRIPTION

Herein is disclosed a method of manufacturing an implantable medicaldevice, such as a stent, by using a thermal treatment process. Theimplantable medical device manufactured in accordance with embodimentsof the present invention may be any suitable medical substrate that canbe implanted in a human or veterinary patient. In the interests ofbrevity, methods of manufacturing a drug delivery or drug eluting stentare described herein. However, one of ordinary skill in the art willunderstand that other medical substrates can be manufactured using themethods of the present invention. For example, the thermal treatmentprocess can be directed to an implantable medical device having a bodythat includes a polymer, and optionally a drug. In one embodiment, thepolymer is biodegradable, bioabsorbable or bioerodable. The embodimentsdirected to a coating are equally applicable to a device, such as astent, made from a polymer or a combination of polymers.

Coating

The thermal treatment process described herein includes exposing (i.e.,heating) a polymer contained in a coating. In one aspect of the presentinvention, the polymer is exposed to a temperature sufficient toincrease the adhesion of a coating to an implantable medical device. Inanother aspect, the polymer is exposed to a temperature sufficient todecrease the release rate of an active agent from a drug coating on animplantable medical device. “Polymer,” “poly,” and “polymeric” areinclusive of homopolymers, copolymers, terpolymers etc., includingrandom, alternating, block, cross-linked, blends and graft variationsthereof. The active agent can be any substance capable of exerting atherapeutic or prophylactic effect.

Some of the embodiments of polymeric coatings are illustrated by FIGS.1A-1H. The Figures have not been drawn to scale, and the thickness ofthe various layers have been over or under emphasized for illustrativepurposes.

Referring to FIG. 1A, a body of a medical substrate 20, such as a stent,is illustrated having a surface 22. A primer layer 24 is deposited onsurface 22. The polymer in primer layer 24 is free of any active agents,although incidental active agent migration into primer layer 24 canoccur. Primer layer 24 can include a poly(lactic acid).

Referring to FIG. 1B, a reservoir layer 26 having a polymer and anactive agent 28 (e.g., 40-O-(2-hydroxy)ethyl-rapamycin, known by thetrade name of everolimus, available from Novartis as Certican™)dispersed in the polymer is deposited on surface 22. Reservoir layer 26can release the active agent when medical substrate 20 is inserted intoa biological lumen.

Referring to FIG. 1C, reservoir layer 26 is deposited on primer layer24. Primer layer 24 serves as an intermediary layer for increasing theadhesion between reservoir layer 26 and surface 22. Increasing theamount of active agent 28 admixed within the polymer can diminish theadhesiveness of reservoir layer 26 to surface 22. Accordingly, using anactive agent-free polymer as an intermediary primer layer 24 allows fora higher active agent content for reservoir layer 26.

The coating of the present invention can also have multiple primer andreservoir layers, the layers alternating between the two types of layersthrough the thickness of the coating. Referring to FIG. 1D, forinstance, medical substrate 20 can have primer layer 24A deposited onsurface 22, followed by reservoir layer 26A deposited on primer layer24A. A second primer layer, primer layer 24B, can then be deposited onreservoir layer 26A. Reservoir layer 26B is deposited over primer layer24B. The different layers through the thickness of the coating cancontain the same or different components. For instance, primer layers24A and 24B can contain the same or different polymers. Furthermore,reservoir layers 26A and 26B can contain the same or different polymersand/or active agents.

The coating can also include a barrier layer. Referring to FIG. 1E,medical substrate 20 is illustrated having reservoir layer 26 depositedon primer layer 24. A barrier layer or rate-reducing membrane 30including a polymer is formed over at least a selected portion ofreservoir layer 26. Barrier layer 30 functions to reduce the rate ofrelease of active agent 28 from medical substrate 20.

As previously shown in FIG. 1B, the coating can be constructed without aprimer layer. For instance, referring to FIG. 1F, medical substrate 20includes cavities or micro-pores 31 formed in the body for releasablycontaining active agent 28. Barrier layer 30 is disposed on surface 22of medical substrate 20, covering cavities 31. Barrier layer 30 canreduce the rate of release of active agent 28 from micropores 31.Furthermore, referring to FIG. 1G, medical substrate 20 is illustratedhaving reservoir layer 26 deposited on surface 22. Barrier layer 30 isformed over at least a selected portion of reservoir layer 26.

One of ordinary skill in the art can appreciate that the coating can beconstructed to provide for a variety of selected release parameters.Such selected patterns may become particularly useful if a combinationof active agents is used, each of which requires a different releaseparameter. FIG. 1H illustrates, for example, medical substrate 20 havinga first reservoir layer 26A disposed on a selected portion of primerlayer 24. First reservoir layer 26A contains a first active agent, e.g.,40-O-(2-hydroxy)ethyl-rapamycin. A second reservoir layer 26B can alsobe disposed on primer layer 24. Second reservoir layer 26B contains asecond active agent, e.g., taxol. First and second reservoir layers 26Aand 26B are covered by first and second barrier layers 30A and 30B,respectively. The particular components of reservoir layers 26A and 26B,and barrier layers 30A and 30B, can be selected so that the release rateof the active agent from first reservoir layer 26A is different or thesame than the release rate of the active agent from second reservoirlayer 26B.

By way of example, and not limitation, primer layer 24 can have anysuitable thickness, examples of which can be in the range of about 0.1to about 10 microns, more narrowly about 0.1 to about 1 micron.Reservoir layer 26 can have any suitable thickness, for example, athickness of about 0.1 microns to about 10 microns, more narrowly about0.5 microns to about 6 microns. The amount of the active agent to beincluded on medical substrate 20 can be further increased by applying aplurality of reservoir layers 24 on top of one another. Barrier layer 30can have any suitable thickness, for example, a thickness of about 0.1to about 10 microns, more narrowly from about 0.25 to about 5 microns.The particular thickness of each layer is based on the type of procedurefor which medical substrate 20 is employed, the amount of the activeagent to be delivered, the rate at which the active agent is to bedelivered, and the thickness of the other coating layers.

Thermal Treatment of a Coating

The method of the present invention includes exposing a polymer on astent or a stent made from a polymer to a thermal treatment. Treatmentincludes heating or exposing the polymer to a temperature andmaintaining the temperature for a duration of time. The duration of timecan be less than a second, a second, minutes, or hours. In someembodiments, maintenance of temperature includes fluctuation in thetemperature. The temperature can be increased or decreased duringtreatment so long as it remains within the range of the selectedtemperature.

In one embodiment, the thermal treatment is conducted on a compositionapplied to the stent, for example immediately after the composition hasbeen applied to the stent while the composition on the stent is remainswet. The composition, for instance, can include a polymer (or polymers)and a solvent (or solvents), and optionally one or more active agents ordrugs. The thermal treatment can be terminated when the coating becomesdry or extended for a period of time subsequent to the drying of thecoating.

In another embodiment, the thermal treatment is conducted subsequent tothe evaporation of the solvent, when the polymer is in a dry form. Inother words, the thermal treatment is conducted when the polymericcoating is a dry coating. “Dry coating” is defined as a coating withless than about 10% residual fluid (e.g., solvent(s) or water) content(w/w). In one embodiment, the coating has less than about 2% residualfluid content (w/w), and more narrowly, less than about 1% residualfluid content (w/w). A coating can also have 0% residual fluid content(w/w).

The amount of residual fluids in the coating can be determined by a KarlFisher, or ThermoGravimetric Analysis (TGA), study. For example, acoated stent can be placed in the TGA instrument, and the weight changecan be measured at 100° C. as an indication of water content, ormeasured at a temperature equal to the boiling temperature of thesolvent used in the coating as an indication of the solvent content.

The stent can undergo the thermal treatment process at any appropriatestage of manufacture, such as before being packaged, or concurrentlywith or subsequent to the stent being secured onto a stent deliverydevice such as a catheter. For instance, the stent coating can beexposed to the appropriate temperature as the stent is being crimpedonto the delivery device, and then further coated with a polymeric drugcoating material.

The heat source/emitter used to thermally treat the coating can be anyapparatus that emits radiation capable of heating the polymeric coating.For example, the heat source can be a cauterizer tip, a RF source, or amicrowave emitter. The heat source can also be a blower that includes aheating device so that the blower can direct a warm gas onto theimplantable device. The gas can be inert (e.g., air, argon, nitrogen,etc.). For example, the heating device can be an electric heaterincorporating heating coils or a system that includes a gas source and acomputer controller to control the temperature of the gas directed atthe stents.

Referring to FIG. 2, a gas system for the thermal treatment process caninclude a gas source 40, a flow controller 42 (e.g., a flow controlleravailable from Eurotherm Control, Inc., Leesburg, Va.), an in-lineheater 44 (e.g., an in-line heater available from Sylvania, Danvers,Mass.), a computer controller 46, an air tight chamber 48 for holding aplurality of stents 50 and an exhaust 52. Computer controller 46 can bein communication with flow controller 42 and in-line heater 44 tocontrol the amount of air and temperature, respectively, which isdelivered to chamber 48. Exhaust 52 can provide a route for unwantedcomponents (e.g., oxygen) to travel after being removed from the stentcoatings. In-line heater 44 can be used to precisely and graduallyincrease the temperature of the gas delivered by gas source 40 to thetemperature used to conduct the thermal treatment.

In one embodiment, a polymeric coating on a stent or a polymeric stentbody is exposed to a temperature for a duration of time sufficient toimprove the mechanical properties of the coating or the stent body. Inone embodiment, the temperature can be above ambient temperature. Thetemperature can also be below the melting temperature of the polymer.For example, a polymer in a primer layer can be exposed to thetemperature to improve the mechanical properties of the primer layer.The thermal treatment can be beneficial because the treatment can causethe primer layer to act as a more effective adhesive tie layer betweenthe stent substrate and subsequently applied layers of polymer. Forexample, as demonstrated by Example 30-34, the heat treatment can causethe primer layer to act as a better adhesive tie layer between ametallic surface of the stent and a drug reservoir layer. Without beingbound by any particular theory, it is believed that the thermaltreatment process of a primer layer can improve adhesion of adrug-delivery coating on a stent by (1) improving the film formation ofthe primer layer (e.g., causing the polymeric primer layer to flow intoimperfections (i.e., microcracks) in the stent substrate); (2) removingresidual stresses in the coating; and/or (3) if the polymer is asemicrystalline polymer, increasing the crystallinity of the polymer.

The thermal treatment can also be beneficial because the treatment canimprove the adhesion between multiple layers of coating material.Without being bound by any particular theory, it is believed that thethermal treatment process will improve adhesion by increasing polymerchain entanglement between the polymers of the different layers.

In another embodiment, polymeric coatings having an active agent can beexposed to a temperature that is greater than ambient temperature and issufficient to decrease the release rate of the active agent from thecoating. The coatings illustrated in FIGS. 1B-H, for instance, can beexposed to the thermal treatment process to decrease the release rate ofthe active agent from the coatings. For example, without thermaltreatment, an active agent (such as 40-O-(2-hydroxy)ethyl-rapamycin) candiffuse from the polymer matrix at a rate that could be too high forcertain clinical conditions. By using the process of the presentinvention, however, the coating can be exposed to a sufficienttemperature effective to decrease the release rate of40-O-(2-hydroxy)ethyl-rapamycin, or analog or derivative thereof, byabout 50% as compared to a control group, as demonstrated in Example 53below.

Without being bound by any particular theory, it is believed that thethermal treatment process can decrease the release rate of the activeagent from the polymeric drug coating by redistributing the microphasedistribution of the active agent in the coating, thereby causing theactive agent to cluster. In particular, the redistribution can decreasethe surface area of the active agent clusters as the clusters areexposed to bodily fluids at the treatment site. Furthermore, the thermaltreatment can decrease the release rate of the active agent by (1)decreasing the free volume in an amorphous polymer; (2) increasing thecrosslinking of the polymer in the coating; and (3) repairing minuteimperfections in the coating such as cracks formed during the initialcoating process.

Furthermore, it is believed that an active agent has a greaterdiffusivity in the amorphous domain of a polymer as compared to thecrystalline domain. Most polymeric materials used for drug deliverystent coatings have some crystallinity and the degree of polymercrystallinity directly affects an active agent's diffusivity due tochanges in free volume and the increase in the volume fraction of thecrystalline phase. Without being bound by any particular theory, it isbelieved that the diffusion rate of the active agent from the polymercan be decreased because heating the polymer increases the percentcrystallinity of the polymer.

Additionally, using the thermal treatment process to treat a polymericdrug coating can increase the manufacturing consistency of drug deliverystents by reducing the variability of the release rate of active agentsamong stents. The thermal treatment process can also reduce the releaserate drift over time. “Release rate drift” refers to the phenomenon inwhich the release rate of an active agent from a polymeric coating canchange over time, for instance, while the stent is in storage. Releaserate drift may occur because of changes in the morphology of a polymericcoating over a period of time, for example by exposure to degradationagents such as oxygen and moisture. As demonstrated by Example 95, byexposing a stent coating to a temperature greater than the glasstransition temperature of the polymer in the coating, the standarddeviation of the mean release rate of the active agent in a 24 hourperiod can be decreased so that the standard deviation is lower than thestandard deviation of the mean release rate for a baseline group ofstents (i.e., stents which have not been subjected to a thermaltreatment process). It is believed that the thermal treatment processcan increase manufacturing consistency by moving a polymeric stentcoating closer to a thermodynamic equilibrium.

In one embodiment, the polymer in the coating is a thermoplasticpolymer. In another embodiment, the polymer in the coating is anamorphous polymer (e.g., D,L-poly(lactic acid)). As understood by thoseof ordinary skill in the art, “amorphous polymers” refer to thosepolymers that are void of crystallinity. Amorphous polymers can bedifferentiated from semicrystalline or crystalline polymers by certainquantifiable characteristics. For example, as further described herein,amorphous polymers do not have a melting temperature (T_(m)) (whilecrystalline and semicrystalline polymers do have a T_(m)), and can havea sharp glass transition. It is believed that the heat treatment of anamorphous polymer in a coating can improve the polymeric film formationon the stent.

In another embodiment of the present invention, the polymer in thecoating is a semicrystalline polymer (e.g., polyvinyl chloride or anethylene vinyl alcohol copolymer). As understood by those of ordinaryskill in the art, “semicrystalline polymers” refer to those polymersthat have at least some crystallinity. Semicrystalline polymers can bedifferentiated from amorphous polymers by certain quantifiablecharacteristics. For example, as further described herein,semicrystalline polymers have a glass transition temperature (T_(g)) anda T_(m).

In one embodiment, a polymeric coating including a semicrystallinepolymer is exposed to the crystallization temperature (T_(c)) of thesemicrystalline polymer or above the T_(c). In one embodiment, thepolymer should have a T_(c) greater than ambient temperature.“Crystallization temperature” refers to the temperature at which asemicrystalline polymer has its highest percent crystallinity. Amorphouspolymers do not exhibit a crystallization temperature. Thecrystallization temperature of ethylene vinyl alcohol copolymer (44 mole% ethylene), for instance, is about 415° K. Other examples ofcrystallization temperatures include 396° K for poly(ethyleneterephthalate) as measured by differential scanning calorimetry (asreported by Parravicini et al., J. Appl. Polym. Sci., 52(7), 875-85(1994)); and 400° K for poly(p-phenylene sulfide) as measured bydifferential scanning calorimetry (as reported by Ding et al.Macromolecules, 29(13), 4811-12 (1996)).

It is believed that the composition components (e.g., solvents) andprocess parameters that are often used to coat stents do not allow formaximum crystallinity in the polymer matrix. If a highly volatilesolvent is included in the composition, for example, then the polymerdoes not have sufficient time to fully crystallize before the solventhas evaporated from the coating. As noted above, it is believed that theprimer layer can act as a more effective adhesive tie layer if thepercent crystallinity of a semicrystalline polymer is increased by theheat treatment. Also, the release rate of a drug from the polymericmatrix can be reduced by increasing the percent of crystallinity of thepolymeric coating (e.g., the reservoir and/or barrier layers.) “Percentcrystallinity” refers to the percentage of the polymer material that isin a crystalline form. It is thought that the methods of the presentinvention can increase the percent crystallinity of the polymer by about5 to 30, more narrowly about 20 to 30 percent crystallinity.

Those of ordinary skill in the art understand that there are severalmethods for determining the percent crystallinity in polymers. Thesemethods are, for example, described in L. H. Sperline, Introduction toPhysical Polymer Science (3^(rd) ed. 2001). The first involves thedetermination of the heat of fusion of the whole sample by calorimetricmethods. The heat of fusion per mole of crystalline material can then beestimated independently by melting point depression experiments. Thepercent crystallinity is then given by heat of fusion of the wholesample divided by the heat of fusion per mole of crystalline materialtimes 100. Representative example of this process and calculation aredescribed in Sarasua et al., Crystallization and Melting Behavior ofPolylactides, Macromolecules 31(12), 3895-3905 (1998); and Reeve et al.,Polylactide Stereochemistry: Effect of Enzymatic Degradability,Macromolecules 27(3), 825-31 (1994) (citing Bloembergen et al., Studiesof Composition and Crystallinity of BacterialPoly(β-hydroxybutyrate-co-β-hydroxyvalerate, Macromolecules 19(11),2865-70 (1986)).

A second method involves the determination of the density of thecrystalline portion via X-ray analysis of the crystal structure, anddetermining the theoretical density of a 100% crystalline material. Thedensity of the amorphous material can be determined from anextrapolation of the density from the melt to the temperature ofinterest. Then the percent crystallinity is given by:

${\% \mspace{14mu} {Crystallinity}} = {\frac{\rho_{exptl} - \rho_{amorph}}{\rho_{100\% \mspace{14mu} {cryst}} - \rho_{amorph}} \times 100}$

where ρ_(expt1) represents the experimental density, and ρ_(amorph) andρ_(100% cryst) are the densities of the amorphous and crystallineportions, respectively.

A third method stems from the fact that X-ray diffraction depends on thenumber of electrons involved and is thus proportional to the density.Besides Bragg diffraction lines for the crystalline portion, there is anamorphous halo caused by the amorphous portion of the polymer. Theamorphous halo occurs at a slightly smaller angle than the correspondingcrystalline peak, because the atomic spacings are larger. The amorphoushalo is broader than the corresponding crystalline peak, because of themolecular disorder. This third method can be quantified by thecrystallinity index, CI, where

${CI} = \frac{A_{c}}{A_{a} + A_{c}}$

and where A_(c) and A_(a) represent the area under the Bragg diffractionline and corresponding amorphous halo, respectively.

In some embodiments of the present invention, the thermal treatmentprocess can be used to heat a polymeric coating on a stent to atemperature equal to or greater than a T_(g) of a polymer included inthe coating. As noted above, both amorphous and semicrystalline polymersexhibit glass transition temperatures. Additionally, if the polymer is asemicrystalline polymer, the polymeric coating can be exposed to atemperature equal to or greater than the T_(g) and less than the T_(m)of the polymer included in the coating. In another embodiment, thepolymer is exposed to a temperature greater than the T_(m) of thepolymer included in the coating. Amorphous polymers do not exhibit aT_(m). In one embodiment, the T_(g) and T_(m) of the polymer is greaterthan ambient temperature.

The polymer can include a crystalline component and an amorphouscomponent. In one embodiment, the polymer is exposed to a temperatureequal to or greater than the T_(g) of one or both components. In anotherembodiment, the polymer is exposed to a temperature less than the T_(m)of the crystalline component. In yet another embodiment, the polymer isexposed to a temperature greater than the T_(m) of the crystallinecomponent.

In yet another embodiment, the polymeric coating is exposed to theannealing temperature of the polymer. “Annealing temperature” refers tothe temperature equal to (T_(g)+T_(m))/2. The annealing temperature forethylene vinyl alcohol copolymer, for instance, is about 383° K. Thepolymeric coating can also be exposed, in another embodiment, to atemperature equal to 0.9 times the T_(m) of the polymer, with the T_(m)expressed in Kelvin (e.g., about 394° K for ethylene vinyl alcoholcopolymer).

The T_(g) is the temperature at which the amorphous domains of a polymerchange from a brittle vitreous state to a plastic state at atmosphericpressure. In other words, the T_(g) corresponds to the temperature wherethe onset of segmental motion in the chains of the polymer occurs. Whenan amorphous or semicrystalline polymer is exposed to an increasingtemperature, the coefficient of expansion and the heat capacity of thepolymer both increase as the temperature is raised, indicating increasedmolecular motion. As the temperature is raised the actual molecularvolume in the sample remains constant, and so a higher coefficient ofexpansion points to an increase in free volume associated with thesystem and therefore increased freedom for the molecules to move. Theincreasing heat capacity corresponds to an increase in heat dissipationthrough movement.

T_(g) of a given polymer can be dependent on the heating rate and can beinfluenced by the thermal history of the polymer. Furthermore, thechemical structure of the polymer heavily influences the glasstransition by affecting mobility. Generally, flexible main-chaincomponents lower the T_(g); bulky side-groups raise the T_(g);increasing the length of flexible side-groups lowers the T_(g); andincreasing main-chain polarity increases the T_(g). Additionally, thepresence of crosslinking polymeric components can increase the observedT_(g) for a given polymer. For instance, FIG. 4 illustrates the effectof temperature and crosslinking on the modulus of elasticity of apolymer, showing that forming cross-links in a polymer can increase theT_(g) and shift the elastic response to a higher plateau—one thatindicates that the polymer has become more glassy and brittle. Moreover,molecular weight can significantly influence T_(g), especially at lowermolecular weights where the excess of free volume associated with chainends is significant.

The T_(m) of a polymer, on the other hand, is the temperature at whichthe last trace of crystallinity in a polymer disappears as a sample isexposed to increasing heat. The T_(m) of a polymer is also known as thefusion temperature (T_(f)). The T_(m) is always greater than the T_(g)for a given polymer.

Like the T_(g), the T_(m) of a given polymer is influenced by thestructure of the polymer. The most influential inter- and intramolecularstructural characteristics include structural regularity, bondflexibility, close-packing ability, and interchain attraction. Ingeneral, high melting points are associated with highly regularstructures, rigid molecules, close-packing capability, strong interchainattraction, or two or more of these factors combined.

Referring to FIG. 3, if the coating polymer is a semicrystallinepolymer, as the polymeric coating is exposed to an increasingtemperature, the polymer exhibits three characteristic thermaltransitions represented by first curve 60, second curve 62 and thirdcurve 64. FIG. 3 illustrates the change in heat capacity (endothermic v.exothermic) of a semicrystalline polymer as the polymer is exposed to anincreasing temperature, as measured by the differential scanningcalorimetry (DSC) method. DSC uses the relationship between heatcapacity and temperature as the basis for determining the thermalproperties of polymers and is further described below.

By way of illustration, when a semicrystalline polymer is exposed to anincreasing temperature, the crystallinity of the polymer begins toincrease as the increasing temperature reaches the T_(g). At and abovethe T_(g), the increased molecular motion of the polymer allows thepolymer chains to move around more to adopt a more thermodynamicallystable relationship, and thereby increase the percent crystallinity ofthe polymer sample. In FIG. 3, the T_(g) is shown as point T_(g) offirst curve 60, which is the temperature at which half of the increasein heat capacity (ΔC_(p)) has occurred. The percent crystallinity thenincreases rapidly after point T_(g) and is maximized at the T_(c) of thepolymer, which is indicated at the point T_(c) (the apex of second curve62). As the temperature continues to increase, the temperatureapproaches the T_(m) of the polymer, and the percent crystallinitydecreases until the temperature reaches the melting temperature of thepolymer (at point T_(m) of curve 64). As noted above, T_(m) is thetemperature where the last trace of crystallinity in the polymerdisappears. The heat of crystallization, ΔH_(c), and the heat of fusion,ΔH_(f), can be calculated as the areas under curves 62 and 64. The heatof crystallization and heat of fusion must be equal, but with oppositesigns.

The T_(g) and/or the T_(m) of the polymer that is to be exposed to thethermal treatment should be determined experimentally in order todetermine which temperatures can be used to thermally treat thepolymeric coating. As used herein, “test polymer” means the polymer thatis measured to determine the T_(g) and/or the T_(m) of the polymer.“Coating polymer” means the polymer that is actually applied as acomponent of the stent coating, in other words, the one or more polymersapplied as components of the primer layer, drug reservoir layer andbarrier layer.

In order to accurately characterize the thermal properties of thecoating polymer, one should consider the number of factors that caninfluence the T_(g) and T_(m) of a polymer. In particular, the factorsinclude (1) the structure of the polymer (e.g., modification of sidegroups and dissimilar stereoregularity); (2) the molecular weight of thepolymer; (3) the molecular-weight distribution (M_(w)/M_(n)) of thepolymer; (4) the crystallinity of the polymer; (5) the thermal historyof the polymer; (6) additives or fillers that are included in thepolymer; (7) the pressure applied to the polymer as the polymer isheated; (8) residual fluids in the polymer; (9) the rate that thepolymer is heated; and (10) the method used to apply the polymer to thesubstrate (e.g., a controlled deposition process as compared to a spraycoating process).

One can account for the foregoing factors by using a test polymer thatis substantially the same as the coating polymer, and is tested undersubstantially the same conditions as the conditions used to conduct thethermal treatment of the polymeric coating. The test polymer should havethe same chemical structure as the coating polymer, and should havesubstantially the same molecular weight and molecular-weightdistribution as the coating polymer. For example, if the polymer is ablend of copolymers or homopolymers, the test polymer should havesubstantially the same percentage of components as the coating polymer.At the same time, the test polymer should have substantially the samecrystallinity as the coating polymer. Methods of determiningcystallinity are discussed herein. Additionally, the composition used toform the test polymer should include the same compounds (e.g., additivessuch as therapeutic substances) and fluids (e.g., solvent(s) and water)that are mixed with the coating polymer. Moreover, the test polymershould have the same thermal history as the coating polymer. The testpolymer should be prepared under the same conditions as the coatingpolymer, such as using the same solvent, temperature, humidity andmixing conditions. The heating rate used for measuring the transitiontemperature of the test polymer should be substantially similar to theheating rate used to conduct the thermal treatment of the polymericcoating. Finally, the method used to apply the test polymer to thesubstrate should be the same as the method used to apply the polymericcoating to the stent.

The T_(g) and T_(m) of the test polymer can be measured experimentallyby testing a bulk sample of the polymer. As understood by one ofordinary skill in the art, a bulk sample of the polymer can be preparedby standard techniques, for example those that are outlined in thedocumentation accompanying the instruments used to measure thetransition temperature of the polymer.

There are several methods that can be used to measure the T_(g) andT_(m) of a polymer. The T_(g) and T_(m) can be observed experimentallyby measuring any one of several basic thermodynamic, physical,mechanical, or electrical properties as a function of temperature.Methods of measuring glass transition temperatures and meltingtemperatures are understood by one of ordinary skill in the art and arediscussed by, for example, L. H. Sperling, Introduction to PhysicalPolymer Science, Wiley-Interscience, New York (3^(rd) ed. 2001); and R.F. Boyer, in Encyclopedia of Polymer Science and Technology, Suppl. Vol.2, N. M. Bikales, ed., Interscience, New York (1977).

The T_(g) of a bulk sample can be observed by measuring the expansion ofthe polymer as the polymer is exposed to increasing temperature. Thisprocess is known as dilatometry. There are at least two ways ofcharacterizing polymers via dilatometry. One way is to measure thelinear expansivity of the polymer sample. Another method involvesperforming volume-temperature measurements, where the polymer isconfined by a liquid and the change in volume is recorded as thetemperature is raised. The usual confining liquid is mercury, since itdoes not swell organic polymers and has no transition of its own throughmost of the temperature range of interest. The results may be plotted asspecific volume versus temperature as shown in FIG. 5, which illustratesa representative example of a dilatometric study of branched poly(vinylacetate). Since the elbow in volume-temperature studies is not sharp(measurements of T_(g) using dilatometric studies show a dispersion ofabout 20-30° C.), the two straight lines below and above the transitionare extrapolated until they meet. The extrapolated meeting point istaken as the T_(g). A representative example of an apparatus that can beused to measure a T_(g) via dilatometric studies is the Dilatometer DIL402 PC (available from Netzsch, Inc., Exton, Pa.).

Thermal methods can also be used to measure the T_(g) of a bulk sample.Two closely related methods are differential thermal analysis (DTA), anddifferential scanning calorimetry (DSC). Both methods yield peaksrelating to endothermic and exothermic transitions and show changes inheat capacity. A representative example of a DTA apparatus is theRheometrics STA 1500 which provides simultaneous thermal analysis viaDTA and DSC.

In addition to the information that can be produced by a DTA, the DSCmethod also yields quantitative information relating to the enthalpicchanges in the polymer (the heat of fusion of the temperature, ΔH_(f)).The DSC method uses a servo system to supply energy at a varying rate tothe sample and the reference, so that the temperatures of the two stayequal. The DSC output plots energy supplied against average temperature.By this method, the areas under the peaks can be directly related to theenthalpic changes quantitatively.

Referring to FIG. 3, the T_(g) can be taken as the temperature at whichone-half of the increase in the heat capacity, ΔC_(p), has occurred. Theincrease in ΔC_(p) is associated with the increased molecular motion ofthe polymer.

A method of separating a transient phenomenon such as a hysteresis peakfrom the reproducible result of the change in heat capacity is obtainedvia the use of modulated DSC. Here, a sine wave is imposed on thetemperature ramp. A real-time computer analysis allows a plot of notonly the whole data but also its transient and reproducible components.Representative examples of modulated DSC apparatuses are those in the QSeries™ DSC product line from TA Instruments, New Castle, Del.

Another representative example of an apparatus that uses DSC as the basetechnology for measuring the T_(g) is a micro thermal analyzer, such asthe μTA™ 2990 product from TA Instruments. A micro thermal analyzer canhave an atomic force microscope (AFM) that is used in conjunction with athermal analyzer. The instrument can be used to analyze individualsample domains identified from the AFM images. In a micro thermalanalyzer such as the μTA™ 2990, the AFM measurement head can contain anultra-miniature probe that functions as a programmable heat source andtemperature sensor. A micro thermal analyzer, therefore, can provideinformation similar to that from traditional thermal analysis, but on amicroscopic scale. For example, the μTA™ 2990 can provide images of asample in terms of its topography, relative thermal conductivity andrelative thermal diffusivity. The μTA™ 2990 can also provide spatialresolution of about 1 μm with a thermal probe and atomic resolution withregular AFM probes. Other advantages of the μTA™ 2990 is that it canheat the polymer sample from ambient to about 500° C. at heating ratesup to 1500° C./minute which allows for rapid thermal characterization(e.g., in less than 60 seconds), and it can hold the sampleisothermically over a broad range of temperatures (e.g., −70 to 300°C.), which allows for thermal characterization over a broad temperaturerange.

Since the notion of the glass-rubber transition stems from a softeningbehavior, mechanical methods can provide very direct determination ofthe T_(g) for a bulk sample. Two fundamental types of measurementprevail: the static or quasi-static methods, and the dynamic methods.For amorphous polymers and many types of semicrystalline polymers inwhich the crystallinity does not approach 100%, stress relaxation,Gehman, and/or Glash-Berg instrumentation provide, through staticmeasurement methods, rapid and inexpensive scans of the temperaturebehavior of new polymers before going on to more complex methods.Additionally, there are instruments that can be employed to measuredynamic mechanical spectroscopy (DMS) or dynamic mechanical analysis(DMA) behavior. A representative example of an apparatus for a DMAmethod is the DMA 242, available from Netzsch, Inc., Exton, Pa.

Another method for studying the mechanical spectra of all types ofpolymers, especially those that are not self-supporting, is torsionalbraid analysis (TBA). In this case the polymer is dipped onto a glassbraid, which supports the sample. The braid is set into a torsionalmotion. The sinusoidal decay of the twisting action is recorded as afunction of time as the temperature is changed. Because the braid actsas a support medium, the absolute magnitudes of the transitions are notobtained; only their temperatures and relative intensities are recorded.

The T_(g) of a bulk sample of a polymer can also be observed byutilizing electromagnetic methods. Representative examples ofelectromagnetic methods for the characterization of transitions inpolymers are dielectric loss (e.g., using the DEA 2970 dielectricanalyzer, available from TA Instruments, New Castle, Del.) andbroad-line nuclear magnetic resonance (NMR).

If the thickness of the coating polymer is ultra thin (i.e., less than 1micron), it may be useful to utilize specialized measuring techniques,at least to compare the results with the values determined by measuringa bulk polymer sample to ensure that the bulk values are not affected bythe thickness of the polymer layer. Specialized techniques may be usefulbecause it has recently been observed that the T_(g) of a polymer can beinfluenced by the thickness of the polymer layer. Researchers, forexample, have observed that polystyrene films on hydrogen-passivated Sihad glass transition temperatures that were lower than the bulk value ifthe thickness of the films was less than 0.04 microns. See Forest etal., Effect of Free Surfaces on the T_(g) of Thin Polymer Films,Physical Review Letters 77(10), 2002-05 (September 1996).

Brillouin light scattering (BLS) can be used to measure the T_(g) of apolymer in an ultra thin film. The ultra thin films can be prepared byspin casting the polymer onto a substrate (e.g., the same substrate usedto support the coating polymer on the stent). A spinning apparatus isavailable, for example, from Headway Research, Inc., Garland, Tex. BLScan also be used to find the T_(g) of a polymer in a bulk sample. In BLSstudies of bulk polymers, one measures the velocity ν_(L) of the bulklongitudinal phonon, where ν_(L)=(C₁₁/ρ)^(1/2), C₁₁ is the longitudinalelastic constant, and ρ is the density. Since C₁₁ is a strong functionof ρ, as the sample temperature is changed, the temperature dependenceof ν_(L) exhibits an abrupt change in slope at the temperature at whichthe thermal expansivity is discontinuous, i.e., the T_(g). For thinfilms, BLS probes the elastic properties through observation offilm-guided acoustic phonons. The guided acoustic modes are referred toas Lamb modes for freely standing films. For further discussion of theapplication of BLS for measuring T_(g), see Forest et al., Effect ofFree Surfaces on the Glass Transition Temperature of Thin Polymer Films,Physical Review Letters 77(10), 2002-05 (September 1996); and Forest etal., Mater. Res. Soc. Symp. Proc. 407, 131 (1996).

The T_(g) of an ultra thin polymer film can also be determined by usingthree complementary techniques: local thermal analysis, ellipsometry andX-ray reflectivity. See, e.g., Fryer et al., Dependence of the GlassTransition Temperature of Polymer Films on Interfacial Energy andThickness, Macromolecules 34, 5627-34 (2001). Using ellipsometry (e.g.,with a Rudolph AUTO EL™ nulling ellipsometer) and X-ray reflectivity(e.g., with a SCINTAG XDS 2000™), the T_(g) is determined by measuringchanges in the thermal expansion of the film. Using local thermalanalysis, on the other hand, the T_(g) is determined by measuringchanges in the heat capacity and thermal conductivity of the film andthe area of contact between a probe and the polymer surface.

Table 1 lists the T_(g) for some of the polymers used in the embodimentsof the present invention. The cited temperature is the temperature asreported in the noted reference and is provided by way of illustrationonly and is not meant to be limiting.

TABLE 1 T_(g) METHOD USED TO POLYMER (° K) CALCULATE T_(g) REFERENCEEthylene vinyl 330 DMA Tokoh et al., Chem. alcohol copolymer Express,2(9), 575-78 (1987) Poly(n-butyl 293 Dilatometry Rogers et al., J. Phys.methacrylate) Chem., 61, 985-90 (1957) Poly(ethylene-co- 263 DSC andScott et al., J. Polym. Sci., (vinyl acetate) DMA Part A, Polym. Chem.,32(3), 539-55 (1994) Poly(ethylene 343.69 DSC Sun et al., J. Polym.Sci., terephthalate) Part A, Polym. Chem., 34(9), 1783-92 (1996)Poly(vinylidene 243 Dielectric Barid et al., J. Mater. Sci., fluoride)relaxation 10(7), 1248-51 (1975) Poly(p-phenylene 361 DSC Ding et al.,Macromolecules, sulfide) 29(13), 4811-12 (1996) Poly(6-aminocaproic 325DSC Gee et al., Polymer, 11, acid) 192-97 (1970) Poly(methyl 367 DSCFernandez-Martin et al., J. methacrylate) Polym. Sci., Polym. Phys. Ed.,19(9), 1353-63 (1981) Poly(vinyl 363 Dilatometry Fujii et al., J. Polym.Sci., alcohol) Part A, 2, 2327-47 (1964) Poly(epsilon- 208 DSC Loefgrenet al., Macromolecules, caprolactone) 27(20), 5556-62 (1994)

As noted above, “polymer” as used herein is inclusive of homopolymers,copolymers, terpolymers etc., including random, alternating, block,cross-linked, blends and graft variations thereof. By using the methodsof measurement described above, one may observe more than one T_(g) forsome of these types of polymers. For example, some polymer blends thatexhibit two phase systems can have more than one T_(g). If the polymerof the coating is a combination or blend of polymers, then the selectedtemperature is determined as previously described. For example, if thecoating is a blend of ethylene vinyl alcohol copolymer and poly(vinylalcohol) the T_(g) of the blend can be calculated by using a DSC method.In some embodiments, the lower T_(g) is the designated T_(g). In anotherembodiment, the higher T_(g) is the designated T_(g).

Additionally, some semicrystalline polymers can have two glasstransitions, especially when they have a higher percent crystallinity.See Edith A. Turi, Thermal Characterization of Polymeric Materials,Academic Press, Orlando, Fla. (1981). Bulk-crystallized polyethylene andpolypropylene, for example, can have two glass transition temperaturesat a relatively high percent crystallinity. The lower of the twotransitions is represented as T_(g)(L), which can be the same as theconventional T_(g) at zero crystallinity. The higher transition isdesignated as T_(g)(U) and becomes more detectable as the crystallinityincreases. The difference, ΔT_(g)=T_(g)(U)−T_(g)(L), tends to approachzero as the fractional crystallinity χ approaches zero.

It has also been reported that block and graft copolymers can have twoseparate glass transition temperatures. For some of these polymers, eachT_(g) can be close to the T_(g) of the parent homopolymer. The followingTable 2 lists the glass transition temperatures for representativeexamples of block and graft copolymers that can be used in the presentinvention. As illustrated by Table 2, most of these block and graftcopolymers exhibit two glass transition temperatures. The citedtemperatures were reported in Black and Worsfold, J. Appl. Polym. Sci.,18, 2307 (1974). The researches from this reference used a thermalexpansion technique to measure the temperatures, and are provided by wayof illustration only.

TABLE 2 Lower Upper Total T_(g) T_(g) M₁ M₂ % M₁ MW (° K) (° K)α-Methylstyrene Vinyl acetate 18 103,000 308 455 α-Methylstyrene Vinylchloride 67 39,000 265 455 α-Methylstyrene Styrene 45 61,000 400 —Styrene Methyl 40 70,000 — 371 methacrylate Styrene Butyl acrylate 46104,000 218 372 Styrene Ethylene oxide 50 40,000 201 373 StyreneIsoprene 50 1,000,000 198 374 Styrene Isobutylene 40 141,000 204 375Methyl Ethyl acrylate 56 162,000 250 388 Methacrylate Methyl Vinylacetate 50 96,000 311 371 Methacrylate Methyl Ethyl 50 104,000 342 379Methacrylate methacrylate

In one embodiment of the present invention, if the polymer exhibits morethan one T_(g), the polymer is exposed to a temperature equal to orgreater than the lowest observed T_(g). It is believed that by exposinga polymer to a temperature equal to or greater than the lowest T_(g),the coating characteristics will be improved because at least some ofthe amorphous domains will be modified during the process. In anotherembodiment, if the polymer in the coating exhibits more than one T_(g),the polymer is exposed to a temperature equal to or greater than thehighest observed T_(g). By exposing the polymer to the highest T_(g), itis believed that one can maximize the improvement in coatingcharacteristics, for example, maximizing polymer adhesion and/orcohesion, or maximizing the drug release rate reduction.

As noted above, in one embodiment, the polymer in the coating can beexposed to a temperature equal to or greater than the T_(g) and lessthan the T_(m) of the polymer. There are several types of methods thatcan be used to measure the T_(m) of a polymer. For example, the T_(m)can be observed by measuring visual, physical, and thermal properties asa function of temperature.

T_(m) can be measured by visual observation by using microscopictechniques. For instance, the disappearance of crystallinity in asemicrystalline or crystalline polymer can be observed with amicroscope, with the sample housed between crossed nicols (i.e., anoptical material that functions as a prism, separating light rays thatpass through it into two portions, one of which is reflected away andthe other transmitted). As a polymer sample is heated, the sharp X-raypattern characteristic of crystalline material gives way to amorphoushalos at the T_(m).

Another way of observing the T_(m) is to observe the changes in specificvolume with temperature. Since melting constitutes a first-order phasechange, a discontinuity in the volume is expected. The T_(m) should givea discontinuity in the volume, with a concomitant sharp melting point.Because of the very small size of the crystallites in bulk crystallizedpolymers, however, most polymers melt over a range of several degrees.The T_(m) is the temperature at which the last trace of crystallinitydisappears. This is the temperature at which the largest and/or most“perfect” crystals are melting.

Alternatively, the T_(m) can be determined by using thermomechanicalanalysis (TMA) that uses a thermal probe (e.g., available from PerkinElmer, Norwalk, Conn.). The T_(m) can also be determined with athermal-based method. For example, a differential scanning calorimetry(DSC) study can be used to determine the T_(m). The same process for DSCas described above for the determination of T_(g) can be used todetermine the T_(m). Referring to FIG. 3, the T_(m) of therepresentative polymer is the peak of curve 64.

Table 3 lists the T_(m) for some of the polymers used in the embodimentsof the present invention. The cited temperature is the temperature asreported in the noted reference and is provided by way of illustrationonly and is not meant to be limiting.

TABLE 3 T_(m) METHOD USED TO POLYMER (° K) CALCULATE T_(m) REFERENCEEthylene vinyl 437.3 DMA Tokoh et al., Chem. alcohol copolymer Express,2(9), 575-78 (1987) Poly(ethylene 526.38 DSC Sun et al., J. Polym. Sci.,terephthalate) Part A, Polym. Chem., 34(9), 1783-92 (1996)Poly(vinylidene 444 Dielectric Barid et al., J. Mater. Sci., fluoride)relaxation 10(7), 1248-51 (1975) Poly(p-phenylene 560 DSC Ding et al.,Macromolecules, sulfide) 29(13), 4811-12 (1996) Poly(6-aminocaproic 498DSC Gee et al., Polymer, 11, acid) 192-97 (1970) Poly(vinyl 513 TMAFujii et al., J. Polym. Sci., alcohol) Part A, 2, 2327-47 (1964)Poly(epsilon- 330.5 DSC Loefgren et al., Macromolecules, caprolactone)27(20), 5556-62 (1994)

One can observe more than one T_(m) while using the standard techniquesto measure T_(m) as described herein. For example, while using a DSCmethod of measuring T_(m), a double melting peak can be observed. It hasbeen suggested that multiple observed melting points can be due to thepresence of two or more distinct crystal or morphological structures inthe initial sample. It has also been suggested that this phenomenon canbe the results of annealing occurring during the measurement process(e.g., during a DSC process) whereby crystals of low perfection melthave time to recrystallize a few degrees above and to remelt. See, e.g.,Sarasua et al., Crystallization and Melting Behavior of Polylactides,Macromolecules 31(12), 3895-3905 (1998). To the extent that more thanone T_(m) is observed, the embodiments using T_(m) herein use thehighest observed T_(m).

In the embodiments of the present invention, the thermal treatmentprocess can be used to improve the mechanical properties of polymericcoatings having various coating structures, for instance, thosestructures illustrated in FIGS. 1A-1H. In the embodiments of the presentinvention, the thermal treatment process can also be used to reduce therelease rate of an active agent from polymeric coatings having variouscoating structures. Referring to FIGS. 1B-1H, for instance, reservoirlayer 26 can be exposed to a temperature sufficient to reduce therelease rate of active agent 28 from the coating. In some embodiments,barrier layer 30 can be treated in lieu of or in addition to thereservoir layer 26.

Referring to FIG. 1A, primer layer 24 can be exposed to the thermaltreatment process before a reservoir layer is applied to medicalsubstrate 20 to improve the mechanical properties of the polymericcoating. By performing the thermal treatment process before applicationof the active agent containing reservoir coating, one can avoid exposingheat sensitive active agents to temperatures that can degrade orotherwise adversely affect the active agent. In yet another embodiment,the thermal treatment process is used to treat a coating having multiplelayers wherein at least one of the layers is a primer layer. Referringto FIG. 1C, for instance, the coating including primer layer 24 andreservoir layer 26 can be heat treated.

In one embodiment, the polymer in primer layer 24 is exposed to atemperature equal to or greater than the T_(g) of the polymer. Inanother embodiment, the polymer in primer layer 24 is exposed to a heattreatment at a temperature range equal to or greater than about theT_(g) and optionally less than about the T_(m) of the polymer. Thedevice should be exposed to the heat treatment for any suitable durationof time that would allow for the formation of the primer coating on thesurface of the device.

In one embodiment, primer layer 24 includes a thermoplastic polymer,such as ethylene vinyl alcohol copolymer, polycaprolactone,poly(lactide-co-glycolide), or poly(hydroxybutyrate). Table 4 lists theT_(g) and T_(m) for some of the polymers that can be used for primerlayer 24. The cited exemplary temperature and time for exposure areprovided by way of illustration and are not meant to be limiting.

TABLE 4 Exemplary T_(g) T_(m) Temperature Exemplary Duration Polymer (°K) (° K) (° K) of Time For Heating ethylene vinyl 330 437.3 413 4 hoursalcohol copolymer polycaprolactone 208 330.5 323 2 hours ethylene vinyl309 336 318 2 hours acetate (e.g., 33% vinyl acetate content) Polyvinyl363 513 438 2 hours alcoholIn other embodiments, the polymer in primer layer 24 is exposed to (1)the T_(c) of the polymer; (2) the annealing temperature of the polymer;(3) a temperature equal to 0.9 times the T_(m) of the polymer, or (4) atemperature equal to or greater than the T_(m) of the polymer.

In another embodiment, the thermal treatment process is used to treat acoating having reservoir layer 26. For example, referring to FIGS.1B-1E, 1G and 1H, the polymer in reservoir layer 26 is exposed to atemperature equal to or greater than the T_(g) of the polymer inreservoir layer 26. The polymer in reservoir layer 26 can also beexposed to a temperature equal to or greater than the T_(g) and,optionally, less than the T_(m) of the polymer. Also, the polymer can beexposed to (1) the T_(c) of the polymer; (2) the annealing temperatureof the polymer; (3) a temperature equal to 0.9 times the T_(m) of thepolymer; or (4) a temperature equal to or greater than the T_(m) of thepolymer. If reservoir layer 26 is covering a primer layer 24, theprocess can also be aimed at exposing the polymer(s) of primer layer 24to a temperature equal to or greater than the T_(g), equal to the T_(c),the annealing temperature, a temperature equal to 0.9 times the T_(m) orequal to or greater than the T_(m) of the polymer(s). If, however, theT_(g) of the primer layer is excessively high or higher than the T_(m)of reservoir layer 26, such high temperatures may adversely affect theactive agents.

The thermal treatment process can also be directed to a polymericcoating having a polymeric reservoir layer 26 covered at least in partby barrier layer 30 as illustrated by FIGS. 1E-1H. Referring to FIG. 1E,for instance, reservoir layer 26 can be deposited on primer layer 24 andcovered by barrier layer 30. The polymer in barrier layer 30 can beexposed to a temperature equal to or greater than the T_(g) of thepolymer in barrier layer 30. A polymer included in barrier layer 30 canalso be exposed to a temperature equal to or greater than the T_(g) and,optionally, less than the T_(m) of the polymer. Also, the polymer can beexposed to (1) the T_(m) of the polymer; (2) the annealing temperatureof the polymer or (3) a temperature equal to 0.9 times the T_(m) of thepolymer. If barrier layer 30 is covering a reservoir layer 26, reservoirlayer 26 can also be heated to a temperature equal to or greater thanthe T_(g) of a polymer in reservoir layer 26, equal to the T_(c) of apolymer in reservoir layer 26, the annealing temperature of a polymer inreservoir layer 26, equal to 0.9 times the T_(m) of the polymer, orequal to or greater than the T_(m) of the polymer.

If the polymeric coating includes multiple layers of coating, thethermal treatment process can be conducted so that polymers in thedifferent layers are heat treated simultaneously. By way of example,referring to FIG. 1G, the polymers in reservoir layer 26 and barrierlayer 30, respectively, can be simultaneously exposed to a temperatureequal to or greater than the T_(g) of the polymers in the two layers.The polymers in reservoir layer 26 and barrier layer 30 can also besimultaneously exposed to (1) a temperature equal to or greater than theT_(g) and less than the T_(m) of the polymers; (2) the T_(c) of thepolymers; (3) the annealing temperature of the polymers; (4) atemperature equal to 0.9 times the T_(m) of the polymers or (5) atemperature equal to or greater than the T_(m) of the polymers. Thepolymers in reservoir layer 26 and barrier layer 30 can besimultaneously exposed to the appropriate temperature if, for instance,the polymer in reservoir layer 26 has the same or substantially the samethermal properties as the polymer in barrier layer 30. For example, thepolymer in reservoir layer 26 can have about the same T_(c) or T_(g) asthe polymer in barrier layer 30. The polymers in reservoir layer 26 andbarrier layer 30 can also be simultaneously exposed to the appropriatetemperature if the temperature used to conduct the thermal treatment issufficiently high to surpass the selected temperature (e.g., annealingtemperature, T_(c), etc.) for each polymer.

The thermal treatment process can also be conducted to selectively treatthe various polymeric layers. For example, one can selectively treat thepolymeric layers by constructing a coating that has layers with polymershaving different thermal properties. The coating illustrated by FIG. 1C,for instance, can be constructed so that the polymer in primer layer 24has different thermal properties than the polymer in reservoir layer 26.In one embodiment, if the polymer in primer layer 24 has a T_(g) that ishigher than the T_(g) of the polymer in reservoir layer 26, thepolymeric coating is exposed to a temperature greater than the T_(g) ofthe polymer in reservoir layer 26, but less than the T_(g) of thepolymer in primer layer 24. This process can also be used if theannealing temperature or T_(c) of the polymer in primer layer 24 isgreater than the annealing temperature or T_(c) of the polymer inreservoir layer 26. In another embodiment, if the polymer in primerlayer 24 has a T_(g) that is lower than the T_(g) of the polymer inreservoir layer 26, the polymeric coating is exposed to a temperaturegreater than the T_(g) of the polymer in primer layer 24, but less thanthe T_(g) of the polymer in reservoir layer 26. This process can also beused if the annealing temperature or T_(c) of the polymer in primerlayer 24 is lower than the annealing temperature or T_(c) of the polymerin reservoir layer 26.

In another example, the coating illustrated by FIG. 1E can beconstructed so that the polymer in reservoir layer 26 has differentthermal properties than the polymer in barrier layer 30. In oneembodiment, if the polymer in reservoir layer 26 has a T_(g) that ishigher than the T_(g) of the polymer in barrier layer 30, the polymericcoating is exposed to a temperature greater than the T_(g) of thepolymer in barrier layer 30, but less than the T_(g) of the polymer inreservoir layer 26. This process can also be used if the annealingtemperature or T_(c) of the polymer in reservoir layer 26 is greaterthan the annealing temperature or T_(c) of the polymer in barrier layer30. In another embodiment, if the polymer in reservoir layer 26 has aT_(g) that is lower than the T_(g) of the polymer in barrier layer 30,the polymeric coating is exposed to a temperature greater than the T_(g)of the polymer in reservoir layer 26, but less than the T_(g) of thepolymer in barrier layer 30. This process can also be used if theannealing temperature or T_(c) of the polymer in reservoir layer 26 islower than the annealing temperature or T_(c) of the polymer in barrierlayer 30.

The heat source can be directed to only certain portions of the stent oronly for certain durations so that the diffusion rates of the activeagent from the polymer differs in various portions of the coating.Referring to FIG. 1H, for example, the polymeric material in barrierlayer 30B can be exposed to a thermal treatment, whereas the polymericmaterial in barrier layer 30A is not. As a result, the release rate ofthe active agent from the polymeric material in barrier 30B can be lowerthan the release rate of the active agent from the polymeric material inbarrier 30A. The release rate difference can result because, forexample, the polymer of barrier layer 30B will have a higher percentcrystallinity than the polymeric material in barrier layer 30A.

In another example, the stent can have two or more segments along thelongitudinal axis of the stent, such as a first segment, a secondsegment and a third segment. The radiation could be directedsubstantially only at the first segment and the third segment, forinstance, by using a cauterizer tip. Alternatively, the radiation couldbe set higher for the first and third segments, or the radiation couldbe directed at the first and third segments for a longer duration thanthe second segment. As a result, the polymer along the first segment andthe third segment would have a greater percent crystallinity than thepolymer along the second segment. Therefore, the diffusion rates of theactive agent from the polymer matrix along the first segment and thethird segment would be less than the diffusion rate along the secondsegment. In one embodiment, the first and third segments can be on theopposing end portions of the stent, the second segment being the middleregion of the stent.

If the polymer in the coating is semicrystalline, the time that thecoating is exposed to radiation can be limited so that the percentcrystallinity is not maximized throughout the entire thickness of thecoating. In other words, the shallower regions of the coating will havea higher percent crystallinity than the deeper regions. The degree ofcrystallinity decreases as a function of the depth of the coating. In aparticular example, if the coating is defined as having four regions,with the fourth region as the deepest, by controlling the thermaltreatment, the first or shallowest region would have a higher percentcrystallinity, followed by the second, third and lastly fourth region,which would have the lowest degree of crystallinity.

The selected duration of the thermal treatment of the polymeric coatingcan depend on the selected exposure temperature, and the thermalcharacteristics of the polymer in the coating, among other environmentalfactors such as the humidity. The duration of the thermal treatment, forinstance, can be from about 30 seconds to about 48 hours. By way ofexample, in a thermal treatment of a coating having ethylene vinylalcohol copolymer and actinomycin D, the polymer can be exposed to atemperature of about 473° K for about 2 minutes, or about 353° K forabout 2 hours.

The exposure temperature should not adversely affect the characteristicsof the polymer or the active agent present in the coating. In order toprevent possible degradation of the active agent or the polymer in thecoating, additives can be mixed with the polymer before or during thecoating process to shift the thermal profile of the polymer (i.e.,decrease the T_(g) and T_(m) of the polymer). For example, aplasticizer, which is usually a low molecular weight nonvolatilemolecule, can be dissolved with the polymer before the applicationprocess. The plasticizer can be an active agent. A representativeexample of an additive is dioctyl phthalate.

The selected duration of the thermal treatment of the reservoir layerand/or barrier layer can depend on the selected exposure temperature,the thermal characteristics of the polymer in the coating, the thermalstability of the active agent and the desired release rate, among otherfactors.

Sterilization of the Stent

After the stent has been coated according to the various embodiments ofthe present invention, the stent can be sterilized by various methods.In an embodiment of the present invention, the particular procedure usedto sterilize the coating can also be modified to conduct the thermaltreating process. For example, an electron beam or a gas sterilizationprocedure can be used to conduct the thermal treating process and tosterilize the coating that has been formed on the stent. Representativeexamples of gas sterilization procedures include those using ethyleneoxide, steam/autoclaving, hydrogen peroxide and peracetic acid. Thesterilization processes can be modified so that the temperature producedduring the process is sufficient to have the desired effect on thecoating, for example, to decrease the release rate of the active agentfrom the polymeric coating, but not significantly degrade the activeagent. For example, for the electron beam sterilization procedure, theexposure temperature is at least a function of dose, dose rate, heatcapacity of the coating material and the degree of insulation of theproduct. These variables can be adjusted so that the coating is exposedto the appropriate temperature.

Forming a Primer Layer

As noted above, the presence of an active agent in a polymeric matrixcan interfere with the ability of the matrix to adhere effectively tothe surface of the device. Increasing the quantity of the active agentreduces the effectiveness of the adhesion. High drug loadings in thecoating can hinder the retention of the coating on the surface of thedevice. A primer layer can serve as a functionally useful intermediarylayer between the surface of the device and an active agent-containingor reservoir coating, or between multiple layers of reservoir coatings.The primer layer provides an adhesive tie between the reservoir coatingand the device—which, in effect, would also allow for the quantity ofthe active agent in the reservoir coating to be increased withoutcompromising the ability of the reservoir coating to be effectivelycontained on the device during delivery and, if applicable, expansion ofthe device.

The primer layer can be formed by applying a polymer or prepolymer tothe stent by conventional methods. For example, a polymer or aprepolymer can be applied by applying the polymer directly onto thestent substrate such as by powder coating or by vapor deposition. In oneembodiment, an unsaturated prepolymer (e.g., an unsaturated polyester oracrylates) is applied to the device, and then heat treated to cause theprepolymer to crosslink.

The polymer or prepolymer can also be applied by depositing a polymercomposition onto the stent. The polymer composition can be prepared bycombining a predetermined amount of a polymer or a prepolymer and apredetermined amount of a solvent or a combination of solvents.“Solvent” is defined as a liquid substance or composition that iscompatible with the components of the composition and is capable ofdissolving the component(s) at the concentration desired in thecomposition. The mixture can be prepared in ambient pressure and underanhydrous atmosphere. If necessary, a free radical or UV initiator canbe added to the composition for initiating the curing or cross-linkingof a prepolymer. Heating and stirring and/or mixing can be employed toeffect dissolution of the polymer into the solvent. The composition canthen be applied by convention methods such as by spraying the stentsubstrate with the composition or dipping the substrate into thecomposition.

The polymers used for the primer material should have a high capacity ofadherence to the surface of an implantable device, such as a metallicsurface of a stent, or a high capacity of adherence to a polymericsurface such as the surface of a stent made of polymer, or a previouslyapplied layer of polymeric material.

Stainless steel such as 316L is a commonly used material for themanufacturing of a stent. Stainless steel includes a chromium oxidesurface layer which makes the stent corrosion resistant and confers, inlarge part, biocompatibility properties to the stent. The chromium oxidelayer presents oxide, anionic groups, and hydroxyl moieties, which arepolar. Consequently, polymeric materials with polar substituents andcationic groups can adhere to the surface.

Representative examples of suitable polymeric materials includepolyisocyanates, unsaturated polymers, high amine content polymers,acrylates, polymers with high content of hydrogen bonding groups, silanecoupling agents, titanates and zirconates.

Representative examples of polyisocyanates include triisocyanurate,alphatic polyisocyanate resins based on hexamethylene diisocyanate,aromatic polyisocyanate prepolymers based on diphenylmethanediisocyanate, polyisocyanate polyether polyurethanes based ondiphenylmethane diisocyanate, polymeric isocyanates based on toluenediisocyanate, polymethylene polyphenyl isocyanate, and polyesterpolyurethanes.

Representative examples of unsaturated polymers include polyesterdiacrylates, polycaprolactone diacrylates, polyester diacrylates,polytetramethylene glycol diacrylate, polyacrylates with at least twoacrylate groups, polyacrylated polyurethanes, and triacrylates. With theuse of unsaturated prepolymers a free radical or UV initiator can beadded to the composition for the thermal or UV curing or cross-linkingprocess. For thermal curing, examples of free radicals initiators arebenzoyl peroxide; bis(2,4-dichlorobenzoyl)peroxide; dicumyl peroxide;2,5-bis(tert-butyl peroxy)-2,5-dimethyl hexane; ammonium persulfate, and2,2′-azobisisobutyronitrile. As is understood by one of ordinary skillin the art, each initiator requires a different temperature to inducedecomposition. For UV curing, examples of initiators include2,2-dimethoxy-2-phenylacetophenone; 1-hydroxycyclohexyl phenyl ketone;benzoin ethyl ether; and benzophenone. These initiators can be activatedby illumination with a medium pressure Hg bulb that contains wavelengthsbetween 250 and 350 nm.

Representative examples of high amine content polymers includepolyethyleneamine, polyallylamine, and polylysine.

Representative examples of acrylates include copolymers of ethylacrylate, methyl acrylate, butyl methacrylate, methacrylic acid, acrylicacid, and cyanoacrylates.

Representative examples of high content of hydrogen bonding grouppolymers include polyethylene-co-polyvinyl alcohol, epoxy polymers basedon the diglycidylether of bisphenol A with amine crosslinking agents,epoxy polymers cured by polyols and lewis acid catalysts, epoxyphenolics, epoxy-polysulfides, ethylene vinyl acetate, melamineformaldehydes, polyvinylalcohol-co-vinyl acetate polymers,resorcinol-formaldehydes, urea-formaldehydes, polyvinylbutyral,polyvinylacetate, alkyd polyester resins, acrylic acid modified ethylenevinyl acetate polymers, methacrylic acid modified ethylene vinyl acetatepolymers, acrylic acid modified ethylene acrylate polymers, methacrylicacid modified ethylene acrylate polymers, anhydride modified ethyleneacrylate butylene, and anhydride modified ethylene vinyl acetatepolymers.

Representative examples of silane coupling agents include3-aminopropyltriethoxysilane and(3-glydidoxypropyl)methyldiethoxysilane.

Representative examples of titanates include tetra-iso-propyl titanateand tetra-n-butyl titanate.

Representative examples of zirconates include n-propyl zirconate andn-butyl zirconate.

Other polymers can be used for the primer material. Representativeexamples of polymers for the primer layer include ethylene vinyl alcoholcopolymer; poly(butylmethacrylate); copolymers of vinyl monomers witheach other and olefins, such as ethylene-methyl methacrylate copolymers,acrylonitrile-styrene copolymers, ABS resins, and ethylene-vinyl acetatecopolymers; poly(hydroxyvalerate); poly(epsilon-caprolactone);poly(lactide-co-glycolide); poly(hydroxybutyrate);poly(hydroxybutyrate-co-valerate); polydioxanone; polyorthoester;polyanhydride; poly(glycolic acid); poly(glycolic acid-co-trimethylenecarbonate); polyphosphoester; polyphosphoester urethane; poly(aminoacids); cyanoacrylates; poly(trimethylene carbonate);poly(iminocarbonate); copoly(ether-esters) (e.g., PEO/PLA); polyalkyleneoxalates; polyphosphazenes; biomolecules, such as fibrin, fibrinogen,cellulose, starch and hyaluronic acid; polyurethanes; silicones;polyesters; polyolefins; polyisobutylene and ethylene-alphaolefincopolymers; acrylic polymers and copolymers; vinyl halide polymers andcopolymers, such as polyvinyl chloride; polyvinyl ethers, such aspolyvinyl methyl ether; polyvinylidene halides, such as polyvinylidenefluoride and polyvinylidene chloride; polyacrylonitrile; polyvinylketones; polyvinyl aromatics, such as polystyrene; polyvinyl esters,such as polyvinyl acetate; polyamides, such as Nylon 66 andpolycaprolactam; alkyd resins; polycarbonates; polyoxymethylenes;polyimides; polyethers; epoxy resins; polyurethanes; rayon;rayon-triacetate; cellulose acetate; cellulose butyrate; celluloseacetate butyrate; cellophane; cellulose nitrate; cellulose propionate;cellulose ethers; poly(lactic acid)-block-polyphosphazene,styrene-block-isobutylene and carboxymethyl cellulose.

Ethylene vinyl alcohol is functionally a very suitable choice ofpolymer. Ethylene vinyl alcohol copolymer refers to copolymerscomprising residues of both ethylene and vinyl alcohol monomers. One ofordinary skill in the art understands that ethylene vinyl alcoholcopolymer may also be a terpolymer so as to include small amounts ofadditional monomers, for example less than about five (5) molepercentage of styrenes, propylene, or other suitable monomers. In auseful embodiment, the copolymer comprises a mole percent of ethylene offrom about 27% to about 47%. Typically, 44 mole percent ethylene issuitable. Ethylene vinyl alcohol copolymer is available commerciallyfrom companies such as Aldrich Chemical Company, Milwaukee, Wis., orEVAL Company of America, Lisle, Ill., or can be prepared by conventionalpolymerization procedures that are well known to one of ordinary skillin the art. The copolymer possesses good adhesive qualities to thesurface of a stent, particularly stainless steel surfaces, and hasillustrated the ability to expand with a stent without any significantdetachment of the copolymer from the surface of the stent.

In one embodiment of the present invention, the polymer in the primerlayer is a biologically degradable polymer. The terms “biologicallydegradable,” “biologically erodable,” “biologically absorbable,” and“biologically resorbable” polymers, which are used interchangeably, aredefined as polymers that are capable of being completely degraded,dissolved, and/or eroded over time when exposed to bodily fluids such asblood and are gradually resorbed, absorbed and/or eliminated by thebody. The processes of breaking down and eventual absorption andelimination of the polymer can be caused, for example, by hydrolysis,metabolic processes, bulk or surface erosion, and the like.

Whenever the reference is made to “biologically degradable,”“biologically erodable,” “biologically resorbable,” and “biologicallyabsorbable” stent coatings and/or polymers forming such stent coatings,it is understood that after the process of degradation, erosion,absorption, or resorption has been completed, no coating will remain onthe stent. In some embodiments, traces or residues may remain. The terms“degradable,” “biodegradable,” or “biologically degradable” are intendedto broadly include biologically degradable, biologically erodable,biologically absorbable, and biologically resorbable coatings and/orpolymers.

In one embodiment, a stent that is made in whole or in part from abiodegradable polymer or a combination of biodegradable polymers issubjected to the thermal treatment in accordance to the variousembodiments of the invention.

In a particular embodiment of the present invention, the biologicallydegradable, erodable, absorbable and/or resorbable polymers that can beused for making the primer layer includes at least a poly(lactic acid).Poly(lactic acid) includes poly(D,L-lactic acid) (DLPLA), poly(D-lacticacid) (DPLA) and poly(L-lactic acid) (LPLA).

The stereochemical composition of the poly(lactic acid) can dramaticallyaffect the properties of the poly(lactic acid). For example, it has beenreported that LPLA can be a semicrystalline polymer that can have aT_(g) of about 67° C., and a T_(m) of about 180° C. On the other hand,DLPLA can be an amorphous polymer that can have a T_(g) of about 58° C.or lower. See, e.g., Reeve et al., Polylactide Stereochemistry: Effectof Enzymatic Degradability, Macromolecules 27(3), 825-31 (1994). Itshould be noted that the amorphous form of PLA may have certainperformance advantages as a component of stent coatings; for example, ithas been found that DLPLA is more readily absorbable under biologicalconditions than LPLA.

Poly(lactic acid) has the formula H—[O—CH(CH₃)—C(O)]_(n)—OH and can beobtained by ring-opening polymerization of lactide (a cyclic dimer oflactic acid), as demonstrated schematically by reaction (I), wherelactide is compound (A) and poly(lactic acid) is compound (B):

The molecular weight of poly(lactic acid) can be for example about30,000 to about 300,000 Daltons. The molecular weight is proportional tothe value of the integer n in the compound (B), which can be for exampleabout 416 to about 4,166. Those having ordinary skill in the art candetermine the conditions under which the transformation of lactide topoly(lactic acid) illustrated by reaction (I) can be carried out.

Alternatively, polymers containing moieties derived from poly(lacticacid) can be also used in addition to or instead of, poly(lactic acid),for making the primer layer. One type of alternative polymers based onpoly(lactic acid) includes derivatives of poly(lactic acid), forexample, hydrolyzed or carboxylated poly(lactic acid), or a blendthereof. Using the hydrolyzed or carboxylated poly(lactic acid) isexpected to result in the increased rate of degradation of the coating.

The hydrolyzed poly(lactic acid) is a polymeric product comprising amixture of the original (unhydrolized) poly(lactic acid) (B) andoligomeric and/or polymeric products of the hydrolysis thereof. Theproducts of hydrolysis can include a complex mixture of oligomers oflactic acid, monomeric lactic acid and other products that can includehydroxylated species. The mixture can contain about 1 mass % to about 20mass % original poly(lactic acids) (B) having the molecular weight asindicated above, and the balance, the products of hydrolysis thereof.The oligomeric and/or polymeric products of hydrolysis of poly(lacticacid) can have an average molecular weight of about 1,000 to about20,000 Daltons.

To obtain the hydrolyzed poly(lactic acid), poly(lactic acid) can behydrolyzed under the condition that can be selected by those havingordinary skill in the art. The process of hydrolysis ispolymer-analogous transformation and can be carried out until themixture of poly(lactic acid) and the products of hydrolysis thereof areobtained, the mixture having a desired ratio between poly(lactic acid)and the products of hydrolysis thereof. The desired ratio can be alsodetermined by those having ordinary skill in the art.

The carboxylated poly(lactic acid) comprises poly(lactic acid)terminated with a carboxyl group and can be obtained by ring-openingpolymerization of lactide (A), in the presence of a butylene acid(HO—R—COOH) serving as a ring opening catalyst as demonstratedschematically by reaction (II), where the carboxylated poly(lactic acid)is compound (C):

Hydroxy acid (HO—R—COOH), the ring-opening catalyst in reaction (II) canbe any suitable butylene acid that can be selected by those havingordinary skill in the art. One example of butylene acid that can be usedis hydroacetic (glycolic) acid.

The carboxylated poly(lactic acid) can be a fully carboxylatedpoly(lactic acid), i.e., can be a 100% product (C). The molecular weightof the fully carboxylated poly(lactic acid) can be about 1,000 to about20,000 Daltons. The fully carboxylated poly(lactic acid) can be obtainedfrom Birmingham Polymers, Inc. of Birmingham, Ala.

The carboxylated poly(lactic acid) can also be in a mixture withoriginal poly(lactic acid) (B). The mixture can contain between about 1mass % to about 20 mass % original poly(lactic acid) (B) having themolecular weight as indicated above, and the balance, the carboxylatedpoly(lactic acid) (C).

Another type of polymer based on poly(lactic acid) that can be used forthe primer layer includes graft copolymers, and block copolymers, suchas AB block-copolymers (“diblock-copolymers”) or ABA block-copolymers(“triblock-copolymers”), or mixtures thereof. The molecular weight ofblocks A can be about 300 to about 40,000 Daltons, more narrowly, about8,000 to about 30,000 Daltons, for example, about 15,000 Daltons. Themolecular weight of blocks B can be about 50,000 to about 250,000Daltons, more narrowly, about 80,000 to about 200,000 Daltons, forexample, about 100,000 Daltons.

The terms “block-copolymer” and “graft copolymer” are defined inaccordance with the terminology used by the International Union of Pureand Applied Chemistry (IUPAC). “Block-copolymer” refers to a copolymercontaining a linear arrangement of blocks. The block is defined as aportion of a polymer molecule in which the monomeric units have at leastone constitutional or configurational feature absent from the adjacentportions. “Graft copolymer” refers to a polymer composed ofmacromolecules with one or more species of block connected to the mainchain as side chains, these side chains having constitutional orconfiguration features that differ from those in the main chain.

The term “AB block-copolymer” is defined as a block-copolymer havingmoieties A and B arranged according to the general formula-{[A-]_(m)-[B]_(n)}—_(x), where each of “m,” “n,” and “x” is a positiveinteger, and m≧2, and n≧2.

The term “ABA block-copolymer” is defined as a block-copolymer havingmoieties A and B arranged according to the general formula-{[A-]_(m)-[B]_(n)-[A-]_(p)}-_(x), where each of “m,” “n,” “p,” and “x”is a positive integer, and m≧2, and n≧2, and p≧2.

The blocks of the ABA and AB block-copolymers need not be linked on theends, since the values of the integers determining the number of A and Bblocks are such as to ensure that the individual blocks are usually longenough to be considered polymers in their own right. Accordingly, theABA block copolymer can be named poly A-block-co-poly B block-co-polyblock-copolymer, and the AB block copolymer can be named polyA-block-co-poly B block-copolymer. Blocks “A” and “B,” can be largerthan the three-block size and can be alternating or random. Note thatthe term “copolymer” encompasses for the purposes of this disclosure apolymer with two or more constituent monomers and does not imply apolymer of only two monomers.

In one embodiment, the block polymers or graft polymers of the presentinvention include a biologically compatible moiety. For example, bothABA and AB block-copolymers can be used to contain the block(s) ofpoly(lactic acid), and block(s) of a biologically compatible moiety,providing the AB or ABA block-copolymer with blood compatibility. Toillustrate, in one embodiment, moiety A is poly(lactic acid) and moietyB is the biocompatible moiety. In another embodiment, moiety B ispoly(lactic acid), and moiety A is the biocompatible moiety. In oneembodiment, the biocompatible moieties are selected in such a way sothat to make the entire ABA and AB block-copolymers biologicallydegradable.

Examples of suitable biocompatible moieties include poly(alkyleneglycols), for example, poly(ethylene-glycol) (PEG), poly(ethyleneoxide), poly(propylene glycol) (PPG), poly(tetramethylene glycol), orpoly(ethylene oxide-co-propylene oxide); lactones and lactides, forexample, ε-caprolactone, β-butyrolactone, δ-valerolactone, or glycolide;poly(N-vinyl pyrrolidone); poly(acrylamide methyl propane sulfonic acid)and salts thereof (AMPS and salts thereof); poly(styrene sulfonate);sulfonated dextran; polyphosphazenes; poly(orthoesters); poly(tyrosinecarbonate); hyaluronic acid; hyaluronic acid having a stearoyl orpalmitoyl substituent group; copolymers of PEG with hyaluronic acid orwith hyaluronic acid-stearoyl, or with hyaluronic acid-palmitoyl;heparin; copolymers of PEG with heparin; a graft copolymer ofpoly(L-lysine) and PEG; or copolymers thereof. A molecular weight of asuitable biocompatible polymeric moiety can be below 40,000 Daltons toensure the renal clearance of the compound, for example, between about300 and about 40,000 Daltons, more narrowly, between about 8,000 andabout 30,000 Daltons, for example, about 15,000 Daltons. Lactones andlactides mentioned above can also replace a part or all of DLPLA in theblock-copolymer, if desired.

Accordingly, one example of the AB block copolymer that can be used ispoly(D,L-lactic acid)-block-poly(ethylene-glycol) (DLPLA-PEG). Onepossible structure of the DLPLA-PEG lock-copolymer is shown by formula(III):

The DLPLA-PEG block-copolymer shown by formula (III) can have a totalmolecular weight of about 30,000 to about 300,000 Daltons, for example,about 60,000 Daltons as measured by the gel-permeation chromatography(GPC) method in tetrahydrofuran. The molecular weight of the PEG blockscan be about 500 to about 30,000 Daltons, for example, about 550Daltons, and the molecular weight of the DLPLA blocks can be about 1,500to about 20,000 Daltons, for example, about 1,900 Daltons. Accordingly,in formula (III), “n” is an integer that can have a value of about 21 toabout 278, and “m” is an integer that can have a value of about 11 toabout 682.

One example of the ABA block copolymer that can be used ispoly(D,L-lactic acid)-block-poly(ethylene-glycol)-block-poly(D,L-lacticacid) (DLPLA-PEG-DLPLA). One possible structure of the DLPLA-PEG-DLPLAblock-copolymer is shown by formula (IV):

The DLPLA-PEG-DLPLA block-copolymer shown by formula (IV) can have atotal molecular weight of about 30,000 to about 300,000 Daltons, forexample, about 60,000 Daltons as measured by a GPC method intetrahydrofuran. The molecular weight of the PEG blocks can be about 500to about 30,000 Daltons, for example, about 7,500 Daltons; and themolecular weight of the DLPLA blocks can be about 1,500 to about 20,000Daltons, for example, one terminal DLPLA block can have the molecularweight of about 3,400 Daltons, and the other terminal DLPLA block canhave the molecular weight of about 10,000 Daltons. Accordingly, informula (IV), “n” is an integer that can have a value of about 21 toabout 278; “m” is an integer that can have a value of about 11 to about682; and “p” is an integer that can have a value of about 21 to about278.

If desired, the positions of the moieties can be switched to obtain aBAB block-copolymer, poly(ethylene-glycol)-block-poly(D,L-lacticacid)-block-poly(ethylene-glycol) (PEG-DLPLA-PEG). One possiblestructure of the PEG-DLPLA-PEG block-copolymer is shown by formula (V):

The PEG-DLPLA-PEG block-copolymer shown by formula (V) can have a totalmolecular weight of about 30,000 to about 300,000 Daltons, for example,about 60,000 Daltons as measured by the GPC method in tetrahydrofuran.The molecular weight of the PEG block can be about 500 to about 30,000Daltons, for example, about 7,500 Daltons; and the molecular weight ofthe DLPLA blocks can be about 1,500 to about 20,000 Daltons.Accordingly, in formula (V), “n” is an integer that can have a value ofabout 21 to about 278; “m” is an integer that can have a value of about11 to about 682, and “p” is an integer that can have a value of about 11to about 682.

Block-copolymers shown by formulae (III-V) can be synthesized bystandard methods known to those having ordinary skill in the art, forexample, copolycondensation of PEG with DLPLA. The process ofcopolycondensation can be catalyzed by an acid or a base, if necessary.

According to one embodiment, hydrolyzed block copolymers of PEG and DPLAcan be used for making the stent coatings. Both AB and ABA and BABblock-copolymers discussed above can be used to obtain the hydrolyzedblock copolymers of PEG and DPLA. The hydrolyze block copolymers of PEGand DPLA are polymeric products comprising a mixture of block copolymersof PEG and DPLA and products of partial hydrolysis thereof. The mixturecan contain about 1 mass % to about 20 mass % unhydrolyzed blockcopolymers of PEG and DPLA and the balance, the products of hydrolysisthereof.

To obtain the hydrolyzed block copolymers of PEG and DPLA, theblock-copolymers can be hydrolyzed under the conditions that can beselected by those having ordinary skill in the art. The process ofhydrolysis can be carried out until the mixture of the block-copolymerand the products of partial hydrolysis thereof is obtained, the mixturehaving a desired ratio between the block-copolymer and the products ofpartial hydrolysis thereof. The desired ratio can be also determined bythose having ordinary skill in the art.

In accordance with other embodiments of the present invention, thebiologically degradable polymer in the primer layer includes:

(a) poly(hydroxybutyrate) (PHB);

(b) poly(hydroxyvalerate) (PHV);

(c) poly(hydroxybutyrate-co-valerate);

(d) poly(caprolactone) (PCL);

(e) poly(lactide-co-glycolide) (PLGA);

(f) poly(glycerol-sebacate) (PGS);

(g) poly(ester amide);

(h) collagen;

(i) elastin;

(j) silk;

(k) AB and ABA block-copolymers of PEG with poly(butylene terephthalate)(PBT), e.g., poly(ethylene-glycol)-block-poly(butylene terephthalate)(PEG-PBT), poly(ethylene-glycol)-block-poly(butyleneterephthalate)-block-poly(ethylene-glycol) (PEG-PBT-PEG), orpoly(butylene terephthalate)-block-poly(ethylene-glycol)-blockpoly(butylene terephthalate) (PBT-PEG-PBT); and

(l) AB and ABA block-copolymers of PEG with PCL, e.g.,poly(ethylene-glycol)-block-poly(caprolactone) (PEG-PCL),poly(ethylene-glycol)-block-poly(caprolactone)-block-poly(ethylene-glycol)(PEG-PCL-PEG), or poly(caprolactone)-block-poly(ethylene-glycol)block-poly(caprolactone) (PCL-PEG-PCL).

Any mixture of compounds of groups (a)-(l) described above can be alsoused. PEG-PBT and PEG-PBT-PEG block copolymers are known under a tradename POLYACTIVE and are available from IsoTis Corp. of Holland. Thesepolymers can be obtained, for example, by trans-esterification ofdibutylene terephthalate with PEG. In POLYACTIVE, the ratio between theunits derived from ethylene glycol and the units derived from butyleneterephthalate can be about 0.67:1 to about 9:1. The molecular weight ofthe units derived from ethylene glycol can be about 300 to about 4,000Daltons, and the molecular weight of the units derived from butyleneterephthalate can be about 50,000 to about 250,000, for example, about100,000 Daltons.

DLPLA-PEG-DLPLA, PEG-DLPLA-PEG, PEG-PBT, PEG-PBT-PEG, PBT-PEG-PBT,PEG-PCL, PEG-PCL-PEG, and PCL-PEG-PCL block copolymers all containfragments with ester bonds. Ester bonds are known to be water-labilebonds. When in contact with slightly alkaline blood, ester bonds aresubject to catalyzed hydrolysis, thus ensuring biological degradabilityof the block-copolymer. One product of degradation of every blockpolymer, belonging to the group DLPLA-PEG-DLPLA, PEG-DLPLA-PEG, PEG-PBT,PEG-PBT-PEG, PBT-PBG-PBT, PEG-PCL, PEG-PCL-PEG, and PCL-PEG-PCL isexpected to be PEG, which is highly biologically compatible.

If a solvent is used to form a polymer composition for application tothe stent, the solvent should be mutually compatible with the polymerand should be capable of placing the polymer into solution at theconcentration desired in the solution. Useful solvents should also beable to expand the chains of the polymer for maximum interaction withthe surface of the device, such as a metallic surface of a stent.Examples of solvent can include, but are not limited to,dimethylsulfoxide (DMSO), dimethyl acetamide (DMAC), chloroform,acetone, water (buffered saline), xylene, acetone, methanol, ethanol,1-propanol, tetrahydrofuran, 1-butanone, dimethylformamide,dimethylacetamide, cyclohexanone, ethyl acetate, methylethylketone,propylene glycol monomethylether, isopropanol, N-methyl pyrrolidinone,toluene and mixtures thereof. Examples of mixtures of solvents include:

(1) DMAC and methanol (e.g., a 50:50 by mass mixture);

(2) water, i-propanol, and DMAC (e.g., a 10:3:87 by mass mixture);

(3) i-propanol and DMAC (e.g., 80:20, 50:50, or 20:80 by mass mixture);

(4) acetone and cyclohexanone (e.g., 80:20, 50:50, or 20:80 by massmixture);

(5) acetone and xylene (e.g., a 50:50 by mass mixture);

(6) acetone, FLUX REMOVER AMS, and xylene (e.g., a 10:50:40 by massmixture); and

(7) 1,1,2-trichloroethane and chloroform (e.g., an 80:20 by massmixture).

By way of example, and not limitation, the polymer can comprise fromabout 0.1% to about 35%, more narrowly about 2% to about 20% by weightof the total weight of the composition, and the solvent can comprisefrom about 65% to about 99.9%, more narrowly about 80% to about 98% byweight of the total weight of the composition. A specific weight ratiois dependent on factors such as the material from which the implantabledevice is made and the geometrical structure of the device.

A fluid can be added to the composition to enhance the wetting of thecomposition for a more uniform coating application. To enhance thewetting of the composition, a suitable fluid typically has a highcapillary permeation. Capillary permeation or wetting is the movement ofa fluid on a solid substrate driven by interfacial energetics. Capillarypermeation is quantitated by a contact angle, defined as an angle at thetangent of a droplet in a fluid phase that has taken an equilibriumshape on a solid surface. A low contact angle means a higher wettingliquid. A suitably high capillary permeation corresponds to a contactangle less than about 90°. FIG. 6A illustrates a fluid droplet 70A on asolid substrate 72, for example a stainless steel surface. Fluid droplet70A has a high capillary permeation that corresponds to a contact angleΦ₁, which is less than about 90°. In contrast, FIG. 6B illustrates afluid droplet 70B on solid substrate 72, having a low capillarypermeation that corresponds to a contact angle Φ₂, which is greater thanabout 90°. The wetting fluid, typically, should have a viscosity notgreater than about 50 centipoise, narrowly about 0.3 to about 5centipoise, more narrowly about 0.4 to about 2.5 centipoise. The wettingfluid, accordingly, when added to the composition, reduces the viscosityof composition.

The wetting fluid should be mutually compatible with the polymer and thesolvent and should not precipitate the polymer. The wetting fluid canalso act as the solvent. Useful examples of the wetting fluid include,but are not limited to, tetrahydrofuran (THF), dimethylformamide (DMF),1-butanol, n-butyl acetate, dimethyl acetamide (DMAC), and mixtures andcombinations thereof. By way of example and not limitation, the polymercan comprise from about 0.1% to about 35%, more narrowly from about 2%to about 20% by weight of the total weight of the composition; thesolvent can comprise from about 19.9% to about 98.9%, more narrowly fromabout 58% to about 84% by weight of the total weight of the composition;the wetting fluid can comprise from about 1% to about 80%, more narrowlyfrom about 5% to about 40% by weight of the total weight of thecomposition. The specific weight ratio of the wetting fluid depends onthe type of wetting fluid employed and type of and the weight ratio ofthe polymer and the solvent. More particularly, tetrahydrofuran used asthe wetting fluid can comprise, for example, from about 1% to about 44%,more narrowly about 21% by weight of the total weight of the solution.Dimethylformamide used as the wetting fluid can comprise, for example,from about 1% to about 80%, more narrowly about 8% by weight of thetotal weight of the solution. 1-butanol used as the wetting fluid cancomprise, for example, from about 1% to about 33%, more narrowly about9% by weight of the total weight of the solution. N-butyl acetate usedas the wetting fluid can comprise, for example, from about 1% to about34%, more narrowly about 14% by weight of the total weight of thesolution. DMAC used as the wetting fluid can comprise, for example, fromabout 1% to about 40%, more narrowly about 20% by weight of the totalweight of the solution.

Table 5 illustrates some examples of suitable combinations for theprimer composition:

TABLE 5 Wetting Polymer Solvent Fluid Initiators EVOH DMSO — — EVOH DMSOTHF — polyester polyurethanes dimethylformamide — — polyesterpolyurethanes dimethylformamide DMAC — polycaprolactone chloroformn-butyl acetate polyacrylates polyurethane ethyl acetate — benzophenonepolyacrylated polyurethane ethyl acetate — 1-hydroxycyclohexyl phenylketone polyethyleneamine H₂O — — methacrylic acid THF — — copolymerethylene vinylacetate methylethylketone — — (e.g., 40% vinyl acetatecontent) aminopropyltriethoxysilane ethanol/water — — 95/5 blend (w/w)(3-glydidoxypropyl) toluene — — methyldiethoxysilane tetra-iso-propyltitanate isopropanol — — (e.g., 0.25% w/w in isopropanol) tetra-n-butyltitanate ethyl acetate — — (e.g., 0.1-5% w/w in ethyl acetate)

With the use of a thermoset polymer, an initiator may be required. Byway of example, epoxy systems consisting of diglycidyl ether ofbisphenol A resins can be cured with amine curatives, thermosetpolyurethane prepolymers can cured with polyols, polyamines, or water(moisture), and acrylated urethane can be cured with UV light. Examples27 and 28 provide illustrative descriptions. If baked, the temperaturecan be above the T_(g) of the selected polymer.

With the use of the inorganic polymers, such as silanes, titanates, andzirconates the composition containing the prepolymer or precursor isapplied and the solvent is allowed to evaporate. Example 29 provides abrief description.

Forming an Active Agent-Containing Coating

The composition containing the active agent can be prepared by firstforming a polymer solution by adding a predetermined amount of a polymerto a predetermined amount of a compatible solvent. The polymer can beadded to the solvent at ambient pressure and under anhydrous atmosphere.If necessary, gentle heating and stirring and/or mixing can be employedto effect dissolution of the polymer into the solvent, for example 12hours in a water bath at about 60° C.

Sufficient amounts of the active agent can then be dispersed in theblended composition of the polymer and the solvent. The active agent canbe mixed with the polymer solution so that the active agent forms a truesolution or becomes saturated in the blended composition. If the activeagent is not completely soluble in the composition, operations includingmixing, stirring, and/or agitation can be employed to effect homogeneityof the residues. The active agent can also be first added to a solventthat is capable of more readily dissolving the active agent prior toadmixing with the polymer composition. The active agent can also beadded so that the dispersion is in fine particles.

The polymer can comprise from about 0.1% to about 35%, more narrowlyfrom about 0.5% to about 20% by weight of the total weight of thecomposition, the solvent can comprise from about 59.9% to about 99.8%,more narrowly from about 79% to about 99% by weight of the total weightof the composition, and the active agent can comprise from about 0.1% toabout 40%, more narrowly from about 1% to about 9% by weight of thetotal weight of the composition. Selection of a specific weight ratio ofthe polymer and solvent is dependent on factors such as, but not limitedto, the material from which the device is made, the geometricalstructure of the device, the type and amount of the active agentemployed, and the release rate desired.

Representative examples of polymers that can be combined with the activeagent for the reservoir layer include the polymers noted above for theprimer layer. Ethylene vinyl alcohol copolymer, for example, isfunctionally a very suitable choice of polymer because ethylene vinylalcohol copolymer allows for good control capabilities of the releaserate of the active agent. As a general rule, an increase in the amountof the ethylene comonomer content decreases the rate that the activeagent is released from the copolymer matrix. The release rate of theactive agent typically decreases as the hydrophilicity of the copolymerdecreases. An increase in the amount of the ethylene comonomer contentincreases the overall hydrophobicity of the copolymer, especially as thecontent of vinyl alcohol is concomitantly reduced. It is also thoughtthat the release rate and the cumulative amount of the active agent thatis released is directly proportional to the total initial content of theagent in the copolymer matrix. Accordingly, a wide spectrum of releaserates can be achieved by modifying the ethylene comonomer content andthe initial amount of the active agent.

Poly(butylmethacrylate) (“PBMA”) and ethylene-vinyl acetate copolymerscan also be especially suitable polymers for the reservoir layer. In oneembodiment, the polymer in the reservoir coating is a mixture of PBMAand an ethylene-vinyl acetate copolymer.

In one embodiment of the invention, the polymer in the reservoir layeris a biologically biodegradable polymer, such as one of the polymerslisted above for formation of the primer layer. The biologicaldegradation, erosion, absorption and/or resorption of a biologicallydegradable, absorbable and/or resorbable polymer are expected to causethe release rate of the drug due to the gradual disappearance of thepolymer that is included in the reservoir layer. By choosing anappropriate degradable polymer the stent coating can be engineered toprovide either fast or slow release of the drug, as desired. Thosehaving ordinary skill in the art can determine whether a stent coatinghaving slow or fast release rate is advisable for a particular drug. Forexample, fast release may be recommended for stent coatings loaded withantimigratory drugs which often need to be released within 1 to 2 weeks.For antiproliferative drugs, slow release may be needed (up to 30 daysrelease time).

Representative examples of solvents include the solvents listed abovefor the primer layer. The active agent may be any substance capable ofexerting a therapeutic or prophylactic effect in the practice of thepresent invention. Exposure of the composition to the active agentshould not adversely alter the active agent's composition orcharacteristic. Accordingly, the particular active agent is selected forcompatibility with the blended composition.

Examples of active agents include antiproliferative substances such asactinomycin D, or derivatives and analogs thereof (manufactured bySigma-Aldrich 1001 West Saint Paul Avenue, Milwaukee, Wis. 53233; orCOSMEGEN available from Merck). Synonyms of actinomycin D includedactinomycin, actinomycin IV, actinomycin I₁, actinomycin X₁, andactinomycin C₁. The bioactive agent can also fall under the genus ofantineoplastic, anti-inflammatory, antiplatelet, anticoagulant,antifibrin, antithrombin, antimitotic, antibiotic, antiallergic andantioxidant substances. Examples of such antineoplastics and/orantimitotics include paclitaxel, (e.g., TAXOL® by Bristol-Myers SquibbCo., Stamford, Conn.), docetaxel (e.g., TAXOTERE®, from Aventis S.A.,Frankfurt, Germany), methotrexate, azathioprine, vincristine,vinblastine, fluorouracil, doxorubicin hydrochloride (e.g., ADRIAMYCIN®from Pharmacia & Upjohn, Peapack N.J.), and mitomycin (e.g., MUTAMYCIN®from Bristol-Myers Squibb Co., Stamford, Conn.). Examples of suchantiplatelets, anticoagulants, antifibrin, and antithrombins includeaspirin, sodium heparin, low molecular weight heparins, heparinoids,hirudin, argatroban, forskolin, vapiprost, prostacyclin and prostacyclinanalogues, dextran, D-phe-pro-arg-chloromethylketone (syntheticantithrombin), dipyridamole, glycoprotein IIb/IIIa platelet membranereceptor antagonist antibody, recombinant hirudin, and thrombininhibitors such as ANGIOMAX™ (bivalirudin, Biogen, Inc., Cambridge,Mass.). Examples of such cytostatic or antiproliferative agents includeangiopeptin, angiotensin converting enzyme inhibitors such as captopril(e.g., CAPOTEN® and CAPOZIDE® from Bristol-Myers Squibb Co., Stamford,Conn.), cilazapril or lisinopril (e.g., PRINIVIL® and PRINZIDE® fromMerck & Co., Inc., Whitehouse Station, N.J.), calcium channel blockers(such as nifedipine), colchicine, proteins, peptides, fibroblast growthfactor (FGF) antagonists, fish oil (omega 3-fatty acid), histamineantagonists, lovastatin (an inhibitor of HMG-CoA reductase, acholesterol lowering drug, brand name MEVACOR® from Merck & Co., Inc.,Whitehouse Station, N.J.), monoclonal antibodies (such as those specificfor Platelet-Derived Growth Factor (PDGF) receptors), nitroprusside,phosphodiesterase inhibitors, prostaglandin inhibitors, suramin,serotonin blockers, steroids, thioprotease inhibitors,triazolopyrimidine (a PDGF antagonist), and nitric oxide. An example ofan antiallergic agent is permirolast potassium. Other therapeuticsubstances or agents which may be appropriate agents include cisplatin,insulin sensitizers, receptor tyrosine kinase inhibitors, carboplatin,alpha-interferon, genetically engineered epithelial cells,anti-inflammatory agents, steroidal anti-inflammatory agents,non-steroidal anti-inflammatory agents, antivirals, anticancer drugs,anticoagulant agents, free radical scavengers, estradiol, antibiotics,nitric oxide donors, super oxide dismutases, super oxide dismutasesmimics, 4-amino-2,2,6,6-tetramethylpiperidine-1-oxyl (4-amino-TEMPO),tacrolimus, dexamethasone, rapamycin, rapamycin derivatives, ABT-578,clobetasol, cytostatic agents, prodrugs thereof, co-drugs thereof, and acombination thereof.

Rapamycin can be a very suitable choice of active agent. Additionally,40-O-(2-hydroxy)ethyl-rapamycin (everolimus), or a functional analog orstructural derivative thereof, can be an especially functional choice ofactive agent. Examples of analogs or derivatives of40-O-(2-hydroxy)ethyl-rapamycin include but are not limited to40-O-(3-hydroxy)propyl-rapamycin and40-O-[2-(2-hydroxy)ethoxy]ethyl-rapamycin, and 40-O-tetrazole-rapamycin.

40-O-(2-hydroxy)ethyl-rapamycin binds to the cytosolic immunophyllinFKBP12 and inhibits growth factor-driven cell proliferation, includingthat of T-cells and vascular smooth muscle cells. The actions of40-O-(2-hydroxy)ethyl-rapamycin occur late in the cell cycle (i.e., lateG1 stage) compared to other immunosuppressive agents such as tacrolimusor cyclosporine which block transcriptional activation of earlyT-cell-specific genes. Since 40-O-(2-hydroxy)ethyl-rapamycin can act asa potent anti-proliferative agent, it is believed that40-O-(2-hydroxy)ethyl-rapamycin can be an effective agent to treatrestenosis by being delivered to a local treatment site from a polymericcoated implantable device such as a stent.

The release rate of 40-O-(2-hydroxy)ethyl-rapamycin can beadvantageously controlled by various methods and coatings as describedherein. In particular, by using the methods and coatings of the presentinvention, the release rate of the 40-O-(2-hydroxy)ethyl-rapamycin, oranalog or derivative thereof, can be less than about 50% in 24 hours.

When the 40-O-(2-hydroxy)ethyl-rapamycin is blended with a polymer forthe reservoir layer, the ratio of 40-O-(2-hydroxy)ethyl-rapamycin, oranalog or derivative thereof, to polymer by weight in the reservoirlayer can be about 1:2.8 to about 1:1. The40-O-(2-hydroxy)ethyl-rapamycin, or analog or derivative thereof, in thereservoir layer can be in the amount of about 50 μg to about 500 μg,more narrowly about 90 μg to about 350 μg, and the polymer is in theamount of about 50 μg to about 1000 μg, more narrowly about 90 μg toabout 500 μg.

The dosage or concentration of the active agent required to produce atherapeutic effect should be less than the level at which the activeagent produces unwanted toxic effects and greater than the level atwhich non-therapeutic effects are obtained. The dosage or concentrationof the active agent required to inhibit the desired cellular activity ofthe vascular region, for example, can depend upon factors such as theparticular circumstances of the patient; the nature of the trauma; thenature of the therapy desired; the time over which the ingredientadministered resides at the vascular site; and if other bioactivesubstances are employed, the nature and type of the substance orcombination of substances. Therapeutically effective dosages can bedetermined empirically, for example by infusing vessels from suitableanimal model systems and using immunohistochemical, fluorescent orelectron microscopy methods to detect the agent and its effects, or byconducting suitable in vitro studies. Standard pharmacological testprocedures to determine dosages are understood by one of ordinary skillin the art.

Forming a Barrier Layer to Reduce the Rate of Release

In some coatings, the release rate of the active agent may be too highto be clinically useful. For example, as shown in Example 58 below, for40-O-(2-hydroxy)ethyl-rapamycin the percentage of40-O-(2-hydroxy)ethyl-rapamycin released from a stent coating without abarrier layer in 24 hours was determined to be 58.55% as measured in aporcine serum release rate procedure. The release rate from the coatingof Example 58 may be too high for a treatment using40-O-(2-hydroxy)ethyl-rapamycin as the active agent. A barrier layer canreduce the rate of release or delay the time at which the active agentis released from the reservoir layer.

In accordance with one embodiment, the barrier layer can be applied on aselected region of the reservoir layer to form a rate reducing member.The barrier layer can be applied to the reservoir layer prior to orsubsequent to the heat treatment. The composition for the barrier layercan be free or substantially free of active agents. Incidental migrationof the active agent into the barrier layer can occur during orsubsequent to the formation of the barrier layer. Alternatively, formaximum blood compatibility, compounds such as poly(ethylene glycol),heparin, heparin derivatives having hydrophobic counterions, orpolyethylene oxide can be added to the barrier layer, or disposed on topof the barrier layer. The addition can be by blending, mixing,conjugation, bonding, etc.

The choice of polymer for the barrier layer can be the same as theselected polymer for the primer layer and/or reservoir layer. The use ofthe same polymer, as described for some of the embodiments,significantly reduces or eliminates any interfacial incompatibilities,such as lack of cohesion, which may exist in the employment of twodifferent polymeric layers.

Polymers that can be used for a barrier layer include the examples ofpolymers listed above for the primer layer and/or reservoir layer.Representative examples of polymers for the barrier layer also includepolytetrafluoroethylene, perfluoro elastomers,ethylene-tetrafluoroethylene copolymer, fluoroethylene-alkyl vinyl ethercopolymer, polyhexafluoropropylene, low density linear polyethyleneshaving high molecular weights, ethylene-olefin copolymers, atacticpolypropylene, polyisobutene, polybutylenes, polybutenes,styrene-ethylene-styrene block copolymers, styrene-butylene-styreneblock copolymers, styrene-butadiene-styrene block copolymers, andethylene methacrylic acid copolymers of low methacrylic acid content.

Ethylene vinyl alcohol copolymer is functionally a very suitable choiceof polymer for the barrier layer. Fluoropolymers are also a suitablechoice for the barrier layer composition. For example, polyvinylidenefluoride (otherwise known as KYNAR™, available from Atofina Chemicals,Philadelphia, Pa.) can be dissolved in acetone, methylethylketone, DMAC,and cyclohexanone, and can optionally be combined with ethylene vinylalcohol copolymer to form the barrier layer composition. Also, solutionprocessing of fluoropolymers is possible, particularly the lowcrystallinity varieties such as CYTOP™ available from Asahi Glass andTEFLON AF™ available from DuPont. Solutions of up to about 15% (wt/wt)are possible in perfluoro solvents, such as FC-75 (available from 3Munder the brand name FLUORINERT™), which are non-polar, low boilingsolvents. Such volatility allows the solvent to be easily and quicklyevaporated following the application of the polymer-solvent solution tothe implantable device.

PBMA and ethylene-vinyl acetate copolymers can also be especiallysuitable polymers for the barrier layer. PBMA, for example, can bedissolved in a solution of xylene, acetone and HFE FLUX REMOVER™(Techspray, Amarillo, Tex.). The polymer in the barrier layer can be amixture of PBMA and an ethylene-vinyl acetate copolymer.

The barrier layer can also be styrene-ethylene/butylene-styrene blockcopolymer. Styrene-ethylene/butylene-styrene block copolymer, e.g.,KRATON™ G-series, can be dissolved in non-polar solvents such as, butnot limited to, toluene, xylene, and decalin.

Other choices of polymers for the rate-limiting membrane include, butare not limited to, ethylene-anhydride copolymers; and ethylene-acrylicacid copolymers having, for example, a mole % of acrylic acid of fromabout 2% to about 25%. The ethylene-anhydride copolymer available fromBynel adheres well to ethylene vinyl alcohol copolymer and thus wouldfunction well as a barrier layer over a reservoir layer made fromethylene vinyl alcohol copolymer. The copolymer can be dissolved inorganic solvents, such as dimethylsulfoxide and DMAC. Ethylene vinylacetate polymers can be dissolved in organic solvents, such as tolueneand n-butyl acetate. Ethylene-acrylic acid copolymers can be dissolvedin organic solvents, such as methanol, isopropyl alcohol, anddimethylsulfoxide.

Yet another choice of polymer for the rate-limiting membrane is across-linked silicone elastomer. Loose silicone and silicone with verylow cross-linking are thought to cause an inflammatory biologicalresponse. However, it is believed that a thoroughly cross-linkedsilicone elastomer, having low levels of leachable silicone polymer andoligomer, is an essentially non-inflammatory substance. Siliconeelastomers, such as Nusil MED-4750™, MED-4755™, or MED2-6640™, havinghigh tensile strengths, for example between 1200 psi and 1500 psi, willlikely have the best durability during crimping, delivery, and expansionof a stent as well as good adhesion to a reservoir layer, e.g., ethylenevinyl alcohol copolymer or the surface of an implantable device.

The composition for a rate-reducing membrane or diffusion barrier layercan be prepared by the methods used to prepare a polymer solution asdescribed above. The polymer can comprise from about 0.1% to about 35%,more narrowly from about 1% to about 20% by weight of the total weightof the composition, and the solvent can comprise from about 65% to about99.9%, more narrowly from about 80% to about 98% by weight of the totalweight of the composition. Selection of a specific weight ratio of thepolymer and solvent is dependent on factors such as, but not limited to,the type of polymer and solvent employed, the type of underlyingreservoir layer, and the method of application.

Forming a Finishing Layer

Depending on the polymer used for the reservoir or barrier layers, itmay be advantageous to form a finishing layer that is especiallybiocompatible on the surface of the coating that is exposed to thebiological lumen when inserted into a patient. The finishing layer canbe formed on the surface of the coating subsequent to the thermaltreatment. Representative examples of biocompatible polymers orbiocompatible agents for the finishing layer include, but are notlimited to polyethylene oxide, poly(ethylene glycol), hyaluronic acid,polyvinyl pyrrolidone, heparin, heparin derivatives such as those havinghydrophobic counterions, and phosphylcholine.

Methods for Applying the Compositions to the Device

The primer composition can first be applied to the stent. Application ofthe composition can be by any conventional method, such as by sprayingthe composition onto the prosthesis, using a controlled depositionsystem or by immersing the prosthesis in the composition. Arepresentative example of a spray coating device is the EFD 780S devicewith VALVEMATE™ 7040 control system (manufactured by EFD Inc., EastProvidence, R.I.). A representative example of a controlled depositionsystem is described in U.S. Pat. No. 6,395,326 to Castro et al. Briefly,the controlled deposition system can include a dispenser that isconfigured to follow the pattern of the stent structures to deposit acoating directed on the surface of the stent. One exemplary type ofdispenser includes an ink jet printhead type dispenser. Anotherexemplary type of a dispenser that can be used is a microinjectorcapable of injecting small volumes ranging from about 2 to about 70 mL,such as NANOLITER™ 2000 available from World Precision Instruments orPneumatic PICOPUMPS™ PV830 with Micropipette available from CellTechnology System.

Operations such as wiping, centrifugation, blowing, or otherweb-clearing acts can also be performed to achieve a more uniformcoating. Briefly, wiping refers to physical removal of excess coatingfrom the surface of the stent; centrifugation refers to rapid rotationof the stent about an axis of rotation; and blowing refers toapplication of air at a selected pressure to the deposited coating. Anyexcess coating can also be vacuumed off the surface of the device.

After the application of the primer composition, the solvent in thecomposition on the stent should be removed before the application of thereservoir layer composition. The solvent can be allowed to evaporate orevaporation can be induced by heating the device at a predeterminedtemperature for a predetermined period of time. The heating can beconducted in an anhydrous atmosphere and at ambient pressure. Theheating can also be conducted under a vacuum condition. In someembodiments, the thermal treatment according to the various embodimentsof the invention can be used before or after removal of the solvent or asignificant amount of the solvent from the primer layer. A dry or wetcoating of the primer layer can therefore be subjected to the thermaltreatment temperature for a duration of time that improves theproperties of the primer layer.

The composition containing the active agent can be applied to adesignated region of the primer coating or the surface of the device. Asnoted above for the primer layer, the solvent can be removed from thecomposition by allowing the solvent to evaporate or heating the stent.The thermal treatment according to the various embodiments of theinvention can be used before or after removal of the solvent or asignificant amount of the solvent from the reservoir layer. A dry or wetcoating of the reservoir layer can therefore be subjected to the thermaltreatment temperature for a duration of time that improves theproperties of the reservoir layer or the underlying primer layer (if aprimer layer is included).

The diffusion barrier layer can be formed on a designated region of theactive agent-containing coating subsequent to the evaporation of thesolvent and the drying of the polymer for the active agent-containingcoating. The above-described processes can be similarly repeated for theformation of the diffusion barrier layer. For instance, the thermaltreatment according to the various embodiments of the invention can beused before or after removal of the solvent or a significant amount ofthe solvent from the barrier layer. A dry or wet coating of the barrierlayer can therefore be subjected to the thermal treatment temperaturefor a duration of time that improves the properties of the barrier layeror the underlying layer(s).

Depending on the coating process, residual water and oxygen may remainin the coating after the baking processes used to remove the solvents.For example, after a coating process that occurs in a 60% relativehumidity coating environment, a coating with ethylene vinyl alcoholcopolymer can have about 2% residual content of water (w/w). Theseresidual components may adversely react with the polymer during thethermal treatment process if they are not removed beforehand. The stentscan advantageously be processed to remove essentially all of the waterand/or free oxygen that may have been absorbed by the composition duringthe coating process. The stents, for example, can be placed in adessicator and then heated in a convection oven to remove any residualwater. The stents can also be placed in a vacuum oven or in a gaschamber before undergoing the thermal treatment process. If a gaschamber is used, the chamber can be in communication with a gas sourcethat provides an inert gas such as nitrogen or argon that can remove thewater and free oxygen in the coating. The duration required for theprocess to remove residual water can be determined by a Karl Fisher, orTGA study.

Examples of the Device

Examples of implantable medical devices for the present inventioninclude self-expandable stents, balloon-expandable stents, stent-grafts,grafts (e.g., aortic grafts), artificial heart valves, cerebrospinalfluid shunts, pacemaker electrodes, and endocardial leads (e.g.,FINELINE™ and ENDOTAK™, available from Guidant Corporation, Santa Clara,Calif.). The underlying structure of the device can be of virtually anydesign. In one embodiment, the underlying structure is made from ametallic material or an alloy. The device, for example, can be made of ametallic material or an alloy such as, but not limited to, cobaltchromium alloy ((ELGILOY™), stainless steel (316L), high nitrogenstainless steel, e.g., BIODUR 108, cobalt chrome alloy L-605, “MP35N,”“MP20N,” ELASTINITE™ (Nitinol), tantalum, nickel-titanium alloy,platinum-iridium alloy, gold, magnesium, or combinations thereof “MP35N”and “MP20N” are trade names for alloys of cobalt, nickel, chromium andmolybdenum available from Standard Press Steel Co., Jenkintown, Pa.“MP35N” consists of 35% cobalt, 35% nickel, 20% chromium, and 10%molybdenum. “MP20N” consists of 50% cobalt, 20% nickel, 20% chromium,and 10% molybdenum.

In another embodiment, the underlying structure is made of a biostablepolymer, or a bioabsorbable, bioerodable or biodegradable polymer. Theunderlying structure, for example, can be made of a polymer such as, butnot limited to, polyanhydrides such as poly(L-lactic acid),poly(D-lactic acid), poly(D,L-lactic acid), poly(L-lacticacid-co-L-aspartic acid), poly(D,L-lactic acid-co-L-aspartic acid) andpoly(maleic acid-co-sebacic acid); poly(amino acid); polyesters such aspoly(caprolactone), poly(glycolic acid), poly(hydroxybutyrate),poly(hydroxyvalerate), poly(hydroxybutyrate-valerate),poly(4-hydroxy-L-proline ester), andpoly(1,10-decanediol-1,10-decanediol dilactide); polyorthoesters;polycyanoacrylates; and polyphosphazene.

In one embodiment, the device is a bioabsorbable stent which is intendedto uphold luminal patency for a duration of time until the stent ispartially or completely eliminated by the body. A bioabsorbable stentcan include an agent in the body of the stent or can have a coatinglayer(s) as described herein. A bioabsorbable stent can be subjected tothe thermal treatments of the invention.

Method of Use

In accordance with the above-described method, the active agent can beapplied to a device, e.g., a stent, retained on the device duringdelivery and released at a desired control rate and for a predeterminedduration of time at the site of implantation. A stent having theabove-described coating layers is useful for a variety of medicalprocedures, including, by way of example, treatment of obstructionscaused by tumors in bile ducts, esophagus, trachea/bronchi and otherbiological passageways. A stent having the above-described coatinglayers is particularly useful for treating occluded regions of bloodvessels caused by abnormal or inappropriate migration and proliferationof smooth muscle cells, thrombosis, and restenosis. Stents may be placedin a wide array of blood vessels, both arteries and veins.Representative examples of sites include the iliac, renal, and coronaryarteries.

Briefly, an angiogram is first performed to determine the appropriatepositioning for stent therapy. Angiography is typically accomplished byinjecting a radiopaque contrasting agent through a catheter insertedinto an artery or vein as an x-ray is taken. A guidewire is thenadvanced through the lesion or proposed site of treatment. Over theguidewire is passed a delivery catheter, which allows a stent in itscollapsed configuration to be inserted into the passageway. The deliverycatheter is inserted either percutaneously, or by surgery, into thefemoral artery, brachial artery, femoral vein, or brachial vein, andadvanced into the appropriate blood vessel by steering the catheterthrough the vascular system under fluoroscopic guidance. A stent havingthe above-described coating layers may then be expanded at the desiredarea of treatment. A post insertion angiogram may also be utilized toconfirm appropriate positioning.

EXAMPLES

The embodiments of the present invention will be illustrated by thefollowing set forth examples.

Example 1

Multi-Link™ stents (available from Guidant Corporation) were cleaned byplacement in an ultrasonic bath of isopropyl alcohol solution for 10minutes. The stents were dried and plasma cleaned in a plasma chamber.An ethylene vinyl alcohol copolymer solution was made. Ethylene vinylalcohol copolymer (herein, “EVOH”) is commonly known by the generic nameEVOH or by the trade name EVAL®. The EVOH solution was made with 1 gramof EVOH and 7 grams of DMSO, making an EVOH:DMSO ratio of 1:7. Themixture was placed in a warm water shaker bath at 60° C. for 24 hours.The solution was cooled and vortexed. The cleaned Multi-Link™ stentswere dipped in the EVOH solution and then passed over a hot plate, forabout 3-5 seconds, with a temperature setting of about 60° C. The coatedstents were heated for 6 hours in an air box and then placed in an ovenat 60° C., under vacuum condition, and for 24 hours. The coated stentswere expanded on a 4.0 mm angioplasty balloon. The coatings remainedintact on the stents. The coatings were transparent giving theMulti-Link™ stents a glossy-like shine.

Example 2

Multi-Link™ stents were cleaned by placement in an ultrasonic bath ofisopropyl alcohol solution for 10 minutes. The stents were dried andplasma cleaned in a plasma chamber. An EVOH solution was made with 1gram of EVOH and 4 grams of DMSO, making an EVOH:DMSO ratio of 1:4.Dexamethasone was added to the 1:4 EVOH:DMSO solution. Dexamethasoneconstituted 9% by weight of the total weight of the solution. Thesolution was vortexed and placed in a tube. The cleaned Multi-Link™stents were attached to mandrel wires and dipped into the solution. Thecoated stents were passed over a hot plate, for about 3-5 seconds, witha temperature setting of about 60° C. The coated stents were cured for 6hours in an air box and then placed in a vacuum oven at 60° C. for 24hours. The above-recited step was repeated twice. The average weight ofthe coating was 0.0003 gram, having an estimated dexamethasone contentof 75 μg per stent. The coated stents were expanded on a 4.0 mmangioplasty balloon. The coatings remained intact on the stents.Verification of coverage and physical properties of the coatings werevisualized using a scanning electron microscope. The coatings weretransparent, giving the Multi-Link™ stents a glossy-like shine.

Example 3

Multi-Link Duet™ stents are cleaned by placement in an ultrasonic bathof isopropyl alcohol solution for 10 minutes. The stents are dried andplasma cleaned in a plasma chamber. The EVOH solution is made with 1gram of EVOH and 4 grams of DMSO, making an EVOH:DMSO ratio of 1:4.Dexamethasone is added to the 1:4 EVOH:DMSO solution. Dexamethasoneconstitutes 9% by weight of the total weight of the solution. Thesolution is vortexed and placed in a tube. The cleaned Multi-Link™stents are attached to mandrel wires and dipped into the solution. Thecoated stents are passed over a hot plate, for about 3-5 seconds, with atemperature setting of about 60° C. The coated stents are cured for 6hours in an air box then placed in a vacuum oven at 60° C. for 24 hours.The single layered dexamethasone/EVOH coated stents are dipped into the1:4 ratio EVOH:DMSO solution, free from dexamethasone. The stents arepassed over the hot plate, cured, and placed in the oven as previouslydescribed. The top coating will provide a barrier layer for controllingthe release of dexamethasone from the drug coated layer. The coatedstents can be expanded on a 4.0 mm angioplasty balloon. It is predictedthat the coatings will remain intact on the stents. The coatings will betransparent, giving the Multi-Link™ stents a glossy-like shine.

Example 4

Multi-Link™ stents were cleaned by placement in an ultrasonic bath ofisopropyl alcohol solution for 10 minutes. The stents were dried andplasma cleaned in a plasma chamber. An EVOH solution was made with 1gram of EVOH and 7 grams of DMSO, making an EVOH:DMSO ratio of 1:7.Vinblastine was added to the 1:7 EVOH:DMSO solution. Vinblastineconstituted 2.5% by weight of the total weight of the solution. Thesolution was vortexed and placed in a tube. The cleaned Multi-Link™stents were attached to mandrel wires and dipped into the solution. Thecoated stents were passed over a hot plate, for about 3-5 seconds, witha temperature setting of about 60° C. The coated stents were cured for 6hours in an air box then placed in a vacuum oven at 60° C. for 24 hours.The above process was repeated twice, having a total of three layers.The average weight of the coating was 0.00005 gram, with an estimatedvinblastine concentration of 12 microgram per stent. Some of the stentswere sterilized by electron beam radiation. The sterilized andunsterilized vinblastine coated stents were tested for a 24 hour elutionperiod by placing one sterilized and one unsterilized stent in 5 ml ofphosphated saline solution (pH 7.4) at room temperature with rotationalmotion. The amount of vinblastine eluted was evaluated by HighPerformance Liquid Chromatography (HPLC) analysis. The results of thistest are given below and plotted in FIG. 7. The data indicates thatelectron beam radiation procedure does not interfere in the release ofvinblastine from EVOH.

Release Profile For Vinblastine -- Unsterilized Time microgram Totalmicrogram microgram Release (Hours) Released Released per Hour 0 0 0 00.5 2.12 2.12 4.24 3 1.91 4.03 0.76 4 0.27 4.30 0.27 6 0.38 4.68 0.19 241.7 6.38 0.09

Release Profile For Vinblastine -- Sterilized Time μg Total μg μgRelease (Hours) Release Released per Hour 0 0 0 0 0.5 2.14 2.14 4.28 31.7 3.84 0.68 4 0.28 4.12 0.28 6 0.26 4.38 0.13 24 2.05 6.43 0.11

Example 5

Multi-Link™ stents were cleaned by placement in an ultrasonic bath ofisopropyl alcohol solution for 10 minutes. The stents were dried andplasma cleaned in a plasma chamber. An EVOH solution was made with 1gram of EVOH and 7 grams of DMSO, making an EVOH:DMSO ratio of 1:7.Cephalotaxin was added to the 1:7 EVOH:DMSO solution. Cephalotaxinconstituted 5% by weight of the total weight of the solution. Thesolution was vortexed and placed in a tube. The cleaned Multi-Link™stents were attached to mandrel wires and dipped into the solution. Thecoated stents were passed over a hot plate, for about 3-5 seconds, witha temperature setting of about 60° C. The coated stents were cured for 6hours in an air box then placed in a vacuum oven at 60° C. for 24 hours.The above process was repeated twice, having a total of three layers.The average weight of the coating was 0.00013 gram, with an estimatedcephalotaxin concentration of 33 μg. The stents were sterilized byelectron beam radiation. Cephalotaxin/EVOH coated stents and EVOH-coatedcontrol stents were implanted in the coronary arteries of 4 pigs,generally in accordance to the procedure set forth in “Restenosis AfterBalloon Angioplasty-A Practical Proliferative Model in Porcine CoronaryArteries” by Robert S. Schwartz, et al., Circulation 82(6):2190-2200,December 1990, and “Restenosis and the Proportional Neointimal Responseto Coronary Artery Injury: Results in a Porcine Model” by Robert S.Schwartz et al, J Am Coll Cardiol; 19:267-74 Feb. 1992. Results of theporcine artery study indicated that there was no significant differencebetween the uncoated, EVOH coated and cephalotaxin coated stents in theamount of neointimal proliferation resulting from arterial injury.

Example 6

Multi-Link Duet™ stents (available from Guidant Corporation) werecleaned by placement in an ultrasonic bath of isopropyl alcohol solutionfor 20 minutes, then air dried. An EVOH stock solution was made with 1gram of EVOH and 7 grams of DMSO, making an EVOH:DMSO ratio of 1:7. Themixture was placed in a warm water shaker bath at 60° C. for 12 hours.The solution was mixed, then cooled to room temperature. A co-solventwas added to the EVOH solution to promote wetting of the struts of theMulti-Link Duet™ stents. One gram of tetrahydrofuran (THF) was mixedwith 1.2 grams of the EVOH:DMSO solution. The cleaned Multi-Link Duet™stents were attached to mandrel wires and dipped into the solution. Thecoated stents were passed over a hot plate, for about 3 to 5 seconds,with a temperature setting of about 60° C. The coated stents were thenheated in a laboratory oven at 90° C. for 4 hours. The thin EVOH coatingadhered to stainless steel without peeling or cracking EVOH forms asuperior primer base coat for other polymers that do not adhere well tostainless steel.

Example 7

Multi-Link Duet™ stents were cleaned in an ultrasonic bath of isopropylalcohol for 20 minutes, then air dried. An EVOH solution was made with 1gram of EVOH and 5 grams of DMSO, making an EVOH:DMSO ratio of 1:5. Themixture was placed in a warm water shaker bath at 60° C. for 12 hours.The solution was mixed, then cooled to room temperature. The dissolvedEVOH:DMSO solution was mixed with 24.6 grams of THF and 19.56 grams ofDMSO. The solution was mixed then placed in the reservoir of an airpressured atomizing sprayer. Multi-Link Duet™ stents were sprayed whilethe stents rotated between 30 to 120 rpm. The spray time was dependentupon the flow rate of the sprayer. A flow rate between 1 to 20 mg/secondrequired a stent to be sprayed between 1 to 30 seconds. The polymercoated Multi-Link Duet™ stents were heated in a forced air convectionoven for 12 hours. The coatings were transparent, giving the Multi-LinkDuet™ stents a glossy-like shine.

Example 8

Multi-Link Duet™ stents were cleaned in an ultrasonic bath of isopropylalcohol for 20 minutes, then air dried. An EVOH stock solution was madehaving an EVOH:DMSO ratio of 1:4. The mixture was placed in a warm watershaker bath at 60° C. for 12 hours. The solution was mixed, then cooledto room temperature. Various co-solvents were examined to determinewhich co-solvent would promote a thicker coating. These co-solvents wereTHF, DMF, 1-butanol, and n-butyl acetate. The formulation for theco-solvents was as follows. Three grams of dissolved EVOH:DMSO solutionwas mixed with 0.9 gram of THF; three grams of dissolved EVOH:DMSOsolution was mixed with 0.39 gram of DMF; three grams of dissolvedEVOH:DMSO solution was mixed with 0.5 gram of 1-butanol; and three gramsof dissolved EVOH:DMSO solution was mixed with 0.68 gram of n-butylacetate. The cleaned Multi-Link Duet™ stents, attached to mandrel wires,were dipped into the solutions. The coated stents were passed over a hotplate, for about 3 to 5 seconds, with a temperature setting of about 60°C. The coated stents were heated in a forced air convection oven for 24hours. A second layer of coating was applied to coated Multi-Link Duet™stents and the stents were heated in the same manner as above. Nodifference was seen between the stents coated with the variousco-solvents (e.g., greater weight of coating or physical appearance).All coated stents were transparent, giving the Multi-Link Duet™ stents aglossy-like shine. No webbing or bridging of the coating was seenbetween the struts of the coated Multi-Link Duet™ stents. The weight ofthe coatings was between 0.2 to 0.27 mg/stent.

Example 9

Multi-Link Duet™ stents are cleaned in an ultrasonic bath of isopropylalcohol for 20 minutes, then air dried. An EVOH stock solution is madehaving an EVOH:DMSO ratio of 1:4. The mixture is placed in a warm watershaker bath at 60° C. for 12 hours. The solution is mixed, then cooledto room temperature. A 9% by weight dexamethasone solution is formulatedas follows: 2.96 grams of the EVOH:DMSO solution is mixed with 0.29 gramof dexamethasone, then 0.9 gram of THF is added. The cleaned Multi-LinkDuet™ stents are attached to mandrel wires and dipped into the solution.The coated stents are passed over a hot plate, for about 3 to 5 seconds,with a temperature setting of about 60° C. The coated stents are curedin a forced air convection oven for 2 hours. A second layer of coatingis applied and cured in the above manner. It is predicted that thecoatings will be transparent, giving the Multi-Link Duet™ stents aglossy-like shine.

Example 10

Multi-Link Duet™ stents are cleaned in an ultrasonic bath of isopropylalcohol for 20 minutes, then air dried. An EVOH stock solution is madehaving an EVOH:DMSO ratio of 1:4. The mixture is placed in a warm watershaker bath at 60° C. for 12 hours. The solution is mixed, then cooledto room temperature. A 9% by weight dexamethasone solution is formulatedas follows: 2.96 grams of the EVOH:DMSO solution is mixed with 0.29 gramof dexamethasone, then 0.9 gram of THF is added. The cleaned Multi-LinkDuet™ stents are attached to mandrel wires and dipped into the solution.The coated stents are passed over a hot plate, for about 3 to 5 seconds,with a temperature setting of about 60° C. The coated stents are curedin a forced air convection oven for 2 hours. A second layer of coatingis applied and cured in the above manner. It is predicted that thecoatings will be transparent, giving the Multi-Link Duet™ stents aglossy-like shine.

Example 11

Multi-Link Duet™ stents were cleaned in an ultrasonic bath of isopropylalcohol for 20 minutes, then air dried. An EVOH stock solution was madehaving an EVOH:DMSO ratio of 1:4. The mixture was placed in a warm watershaker bath at 60° C. for 12 hours. The solution was mixed, then cooledto room temperature. A 4.75% by weight actinomycin D solution wasformulated as follows: 600 milligrams of the EVOH:DMSO solution wasmixed with 40 milligrams of actinomycin D, then 200 milligrams of THFwas added. The cleaned Multi-Link Duet™ stents were attached to mandrelwires and dipped into the solution. The coated stents were passed over ahot plate, for about 3 to 5 seconds, with a temperature setting of about60° C. The coated stents were cured in a forced air convection oven for2 hours. A second layer of coating was applied and cured in the abovemanner.

Example 12

Multi-Link Duet™ stents were cleaned in an ultrasonic bath of isopropylalcohol for 20 minutes, then air dried. An EVOH stock solution was madehaving an EVOH:DMSO ratio of 1:4. The mixture was placed in a warm watershaker bath at 60° C. for 12 hours. The solution was mixed, then cooledto room temperature. A 3.60% by weight actinomycin D solution wasformulated as follows: 600 milligrams of the EVOH:DMSO solution wasmixed with 40 milligrams of actinomycin D, then 480 milligrams of DMFwas added. The cleaned Multi-Link Duet™ stents were attached to mandrelwires and dipped into the solution. The coated stents were passed over ahot plate, for about 3 to 5 seconds, with a temperature setting of about60° C. The coated stents were cured in a forced air convection oven for2 hours. A second layer of coating was applied and cured in the abovemanner.

Example 13

Multi-Link Duet™ stents were cleaned in an ultrasonic bath of isopropylalcohol for 20 minutes, then air dried. An EVOH stock solution was madehaving an EVOH:DMSO ratio of 1:4. The mixture was placed in a warm watershaker bath at 60° C. for 12 hours. The solution was mixed, then cooledto room temperature. A 6.45% by weight actinomycin D solution wasformulated as follows: 680 milligrams of the EVOH:DMSO solution wasmixed with 80 milligrams of actinomycin D, then 480 milligrams of DMFwas added. The cleaned Multi-Link Duet™ stents were attached to mandrelwires and dipped into the solution. The coated stents were passed over ahot plate, for about 3 to 5 seconds, with a temperature setting of about60° C. The coated stents were cured in a forced air convection oven for2 hours. A second layer of coating was applied and cured in the abovemanner.

Example 14

Multi-Link Duet™ stents are cleaned in an ultrasonic bath of isopropylalcohol for 20 minutes, then air dried. An EVOH stock solution is madehaving an EVOH:DMSO ratio of 1:40. The mixture is placed in a warm watershaker bath at 60° C. for 12 hours. The solution is mixed, then cooledto room temperature. A 0.60% by weight actinomycin D solution can beformulated as follows: 4920 milligrams of the EVOH:DMSO solution ismixed with 40 milligrams of actinomycin D, then 2000 milligrams of THFis added. The cleaned Multi-Link Duet™ stents can be sprayed upon by theabove formulation. The coated stents are cured in a forced airconvection oven for 2 hours. A second layer of coating is applied andcured in the above manner.

Example 15 Inhibition of SMC Proliferation with Actinomycin D

Medial smooth muscle cells (SMC) were isolated from rat aorta andcultured according to explant methods known to one of ordinary skill inthe art. Cells were harvested via trypsinization and subcultivated.Cells were identified as vascular SMC through their characteristichill-and-valley growth pattern as well as indirect immunofluorescencewith monoclonal anti SMC α-actin. Studies were performed with cells atpassage 3-4. SMC monolayers were established on 24 well culture dishes,scrape wounded and treated with actinomycin D, mytomycin and docetaxel.The cells were exposed to the drug solution of different concentrationsfor 2 hours and then washed with buffered saline solution. Theproliferation of the cells was quantified by standard technique ofthymidine incorporation. The results from the study are tabulated inFIG. 8.

The IC₅₀ (concentration at which 50% of the cells stop proliferating) ofactimomycin D was 10⁻⁹M as compared to 5×10⁻⁵M for mitomycin and 10⁻⁶Mfor docetaxel. Actinomycin D was the most potent agent to prevent SMCproliferation as compared to other pharmaceutical agents.

Example 16 Reduction in Restenosis in the Porcine Coronary Artery Model

Porcine coronary models were used to assess the degree of the inhibitionof neointimal formation in the coronary arteries of a porcine stentinjury model by actinomycin D, delivered with a microporous ballooncatheter (1×10⁶ pores/mm² with sizes ranging from 0.2-0.8 micron).

The preclinical animal testing was performed in accordance with the NIHGuide for Care and Use of Laboratory Animals. Domestic swine wereutilized to evaluate effect of the drug on the inhibition of theneointimal formation. Each testing procedure, excluding the angiographicanalysis at the follow-up endpoints, was conducted using steriletechniques. During the study procedure, the activated clotting time(ACT) was monitored regularly to ensure appropriate anticoagulation.Base line blood samples were collected for each animal before initiationof the procedure. Quantitative coronary angiographic analysis (QCA) andintravascular ultrasound (IVUS) analysis was used for vessel sizeassessment.

The vessels at the sites of the delivery were denuded by inflation ofthe PTCA balloons to 1:1 balloon to artery ratio and moving the balloonsback and forth 5 times. The drug was delivered to the denuded sites at3.5 atm (3.61 Kg/sq cm) for 2 minutes using the microporous ballooncatheters before stent deployment. The average volume of delivery wasabout 3.3+/−1.2 ml. Following drug delivery, stents were deployed at thedelivery site such that final stent to artery ratio was 1.1:1.

QCA and IVUS analyses were used for stent deployment guidance.Pre-stenting IVUS measurements of the lumen size at the targeted vesselsites were performed for determination of the balloon (size) inflationpressure. Quantitative analysis of the stented coronary arteries tocompare pre-stenting, post-stenting, follow-up minimal luminaldiameters, stent recoil, and balloon/stent to artery ratio wereperformed. Following stent implantation and final angiogram, all deviceswere withdrawn and the wounds closed; the animals were allowed torecover from anesthesia as managed by the attending veterinarian oranimal care professionals at the research center.

Upon return to the research laboratory at the 28-day endpoint,angiographic assessments were performed. Coronary artery blood flow wasassessed and the stented vessels were evaluated to determine minimallumen diameter. The animals were euthanized following this procedure atthe endpoint. Following euthanasia, the hearts were pressure perfusionfixed with formalin and prepared for histological analysis, encompassinglight microscopy, and morphometry. Morphometric analysis of the stentedarteries included assessment of the position of the stent struts anddetermination of vessel/lumen areas, percent (%) stenosis, injuryscores, intimal and medial areas and intima/media ratios. Percentstenosis is quantitated by the following equation:

100(IEL area−lumen area)/IEL area

where IEL is the internal elastic lamia.

The control group of animals received delivery of water instead of thedrug. The test group of animals received actinomycin D in two differentconcentration of 10⁻⁵M and 10⁻⁴M. The results of the study are tabulatedin Table 6. The percent stenosis in the treated groups (32.3+/−11.7) wassignificantly decreased as compared to the control groups (48.8+/−9.8).FIGS. 9A and 9B illustrate sample pictures of the histology slides ofthe coronary vessels from the control and the Dose 1 group,respectively.

TABLE 6 CONTROL DOSE 1 DOSE 2 t test ANGIOGRAPHIC 0M 1E−05M 1E−04M(significant if p < 0.05) DATA (QCA) (n = 9) (n = 10) (n = 7) p~ p*Percent Diameter 48.8 +/− 9.8 36.8 +/− 9.7 32.3 +/− 11.7 0.02 0.01Stenosis HISTOMOR- CONTROL DOSE 1 DOSE 2 t test PHOMETRIC 0M 1E−05M1E−04M (significant if p < 0.05) DATA (n = 27) (n = 30) (n = 21) p~ p*Percent Stenosis 63.4 +/− 12.7 51.8 +/− 13.8 54.1 +/− 11.7 0.002 0.01(IEL area-lumen area)/IEL area Residual Lumen 0.36 +/− 0.16 0.49 +/−0.14 0.46 +/− 0.08 0.002 0.01 (Lumen area)/ IEL area ~comparison betweencontrol and Dose 1 *comparison between control and Dose 2

The results of the in vitro and in vivo standard test proceduresdemonstrate that actinomycin D is useful for the treatment ofhyper-proliferative vascular disease. Specifically, actinomycin D isuseful for the inhibition of smooth muscle cell hyperplasia, restenosisand vascular occlusion in a mammal, particularly occlusions following amechanically mediated vascular trauma or injury.

Example 17

Multi-Link Duet™ stents (13 mm in length) were cleaned in an ultrasonicbath of isopropyl alcohol for 20 minutes, then air dried. An EVOH stocksolution was made having an EVOH:DMSO ratio of 1:4. The mixture wasplaced in a warm water shaker bath at 60° C. for 12 hours. The solutionwas mixed, then cooled to room temperature. A 5.06% by weightactinomycin D solution was formulated as follows: 40 milligrams ofactinomycin D was dissolved in 150 milligrams of THF, then 600milligrams of the EVOH:DMSO was added. The cleaned Multi-Link Duet™stents were attached to mandrel wires and dipped into the solution. Thecoated stents were passed over a hot plate, for about 3 to 5 seconds,with a temperature setting of about 60° C. The coated stents were curedin a forced air convection oven at 60° C. for 1 hour. A second layer ofcoating was applied in the above manner and cured in a forced airconvection oven at 60° C. for 4 hours. An average coating weight ofabout 260 micrograms and an average actinomycin D loading of about 64micrograms was achieved.

Example 18

Multi-Link Duet™ stents (13 mm in length) were cleaned in an ultrasonicbath of isopropyl alcohol for 20 minutes, then air dried. An EVOH stocksolution was made having an EVOH:DMSO ratio of 1:4. The mixture wasplaced in a warm water shaker bath at 60° C. for 12 hours. The solutionwas mixed, then cooled to room temperature. A 3.75% by weightactinomycin D solution was formulated as follows: 60 milligrams ofactinomycin D was dissolved in 310 milligrams of DMF, then 1.22 grams ofEVOH:DMSO solution was added. The cleaned Multi-Link Duet™ stents wereattached to mandrel wires and dipped into the solution. The coatedstents were passed over a hot plate, for about 3 to 5 seconds, with atemperature setting of about 60° C. The coated stents were cured in aforced air convection oven at 60° C. for 1 hour. A second layer ofcoating was applied in the above manner and cured in a forced airconvection oven at 60° C. for 4 hours. An average coating weight ofabout 270 micrograms with an average actinomycin D content of about 51micrograms was achieved.

Example 19

Multi-Link Duet™ stents were cleaned in an ultrasonic bath of isopropylalcohol for 20 minutes, then air dried. An EVOH stock solution was madehaving an EVOH:DMSO ratio of 1:4. The mixture was placed in a warm watershaker bath at 60° C. for 12 hours. The solution was mixed, then cooledto room temperature. A 6.1% by weight actinomycin D solution wasformulated as follows: 100 milligrams of actinomycin D was dissolved in310 milligrams of DMF, then 1.22 grams of EVOH:DMSO was added. Thecleaned Multi-Link Duet™ stents were attached to mandrel wires anddipped into the solution. The coated stents were passed over a hotplate, for about 3 to 5 seconds, with a temperature setting of about 60°C. The coated stents were cured in a forced air convection oven at 60°C. for 1 hour. A second layer of coating was applied in the above mannerand cured in a forced air convection oven at 60° C. for 4 hours. Anaverage coating weight of about 250 micrograms and an averageactinomycin D loading of about 75 micrograms was achieved.

Example 20

Multi-Link Duet™ stents are cleaned in an ultrasonic bath of isopropylalcohol for 20 minutes, then air dried. An EVOH stock solution is madehaving an EVOH:DMSO ratio of 1:40. The mixture is placed in a warm watershaker bath at 60° C. for 12 hours. The solution is mixed, then cooledto room temperature. A 0.60% by weight actinomycin D solution can beformulated as follows: 4920 milligrams of the EVOH:DMSO solution ismixed with 40 milligrams of actinomycin D, then 2000 milligrams of THFis added. The cleaned Multi-Link Duet™ stents can be sprayed upon by theabove formulation. The coated stents are cured in a forced airconvection oven 60° C. for 15 minutes. Additional layers of the coatingare applied and cured in the above manner. The final curing step for thecoated stents is conducted for about 4 hours.

Example 21

A stainless steel stent can be spray coated with a formulation of EVOHand a drug, as previously described in any of the above examples. Adiffusion barrier composition can be formulated with 2 grams of EVOHblended with 20 grams of dimethylsulfoxide. 2.2 grams of fumed silicacan be added and dispersed with a high shear process. With constantagitation, 50 grams of tetrahydrofuran and 30 grams of dimethylformamideare admixed with the blend. The stent, having the EVOH coating, can beimmersed in the diffusion barrier composition to form a layer.

Example 22

A stainless steel stent can be spray coated with a formulation of EVOHand a drug, as previously described in any of the above examples. Adiffusion barrier formulation can be made by dissolving 8 grams of EVOHinto 32 grams of dimethylsulfoxide. To this is added 14 grams of rutiletitanium dioxide and 7 grams more of dimethylsulfoxide. The particlescan be dispersed using a ball mill. The final solution is diluted with39 grams of tetrahydrofuran, added slowly with constant agitation. It ispredicted that the diffusion barrier will reduce the rate at which thedrug is released from the stent.

Example 23

A stainless steel stent can be coated with a formulation of EVOH and adrug, as previously described in any of the above examples. A diffusionbarrier formulation can be made by dissolving 8 grams of EVOH in 32grams of dimethylsulfoxide. 10.5 grams of solution precipitatedhydroxyapatite can be added to the blend. The particles can be dispersedusing a rotor stator mixer. With constant agitation, 30 grams oftetrahydrofuran can be added. The stent can be coated by immersionfollowed by centrifugation.

Example 24

A stent can be coated with a formulation of EVOH and a drug, aspreviously described in any of the above examples. 8 grams of EVOH canbe added 50 grams of dimethylsulfoxide and the polymer can be dissolvedby agitation and heat. Four grams of lamp black can be added anddispersed in a ball mill. 60 grams of dimethyl sulfoxide and 110 gramsof tetrahydrofuran are slowly added while stirring. The stent can bespray coated.

Example 25

A stent can be coated with a formulation of EVOH and a drug, aspreviously described in any of the above examples. Colloidal gold can beprepared by reduction of tetrachloroauric acid with sodium citrate inaqueous solution. The solution can be exchanged by rinsing withtetrahydrofuran. Eight grams of EVOH can be dissolved in 32 grams ofdimethylsulfoxide. To this is added a solution of 77 grams of colloidalgold in 32 grams of tetrahydrofuran. The stent can be coated by a dipcoating process.

Example 26

In vivo data is provided illustrated positive remodeling caused by theapplication of actinomycin D. Stents coated with EVOH impregnated withactinomycin D and a control group of stents coated with EVOH free fromactinomycin D were implanted in porcine coronary arteries. The animalswere sacrificed at the end of 28 days. The EEL area of the actinomycinD-loaded vessels was statistically significantly greater than the EELarea of the control vessels. The index of remodeling was 1.076(8.54/7.94).

Condition Mean Area Std Dev IEL Drug coated(Act-D in EVOH) 7.47 0.89Control (EVOH) 6.6 0.61 p value 0.0002 Statistical significantdifference EEL (external elastic lamia) Drug coated(Act-D in EVOH) 8.540.87 Control (EVOH) 7.94 0.73 p value 0.014 Statistical significantdifference

EEL Area (mm²) Actinomycin ID # Control ID # D ID # EVOH 48 LCX d 6.396663 LCX d 7.4498 63 LAD d 8.3037 48 LCX m 7.4601 63 LCX m 8.2509 63 LAD m8.8545 48 LCX p 7.3063 63 LCX p 7.7342 63 LAD p 9.4698 49 LAD d 8.557363 RCA d 7.9207 64 LCX d 7.8063 49 LAD m 8.5187 63 RCA m 6.9926 64 LCX m7.1117 49 LAD p 6.6346 63 RCA p 8.3883 64 LCX p 7.2411 58 LAD d 8.607865 LAD d 7.8546 64 RCA d 8.3383 58 LAD m 8.1674 65 LAD m 9.2545 64 RCA m8.0793 58 LAD p 8.3775 65 LAD p 9.2515 64 RCA p 8.3652 59 LCA d 8.305468 LAD d 8.7854 65 LCX d 6.4638 59 LCX m 7.3713 68 LAD m 9.5164 65 LCX m7.1493 59 LCX p 7.8662 68 LAD p 9.1504 65 RCA d 8.5955 59 RCA d 7.371469 LCX d 9.6679 65 RCA m 8.0855 59 RCA m 6.6783 69 LCX m 9.1237 65 RCA p8.4785 59 RCA p 7.4707 69 LCX p 9.9849 68 LCX d 8.4723 62 LCX d 7.878469 RCA d 9.4765 68 LCX m 7.8382 62 LCX m 7.5318 69 RCA m 7.4424 68 LCX p8.0570 62 LCX p 6.2647 69 RCA p 9.1462 68 RCA d 8.4840 62 RCA d 8.324070 LCX d 8.9504 68 RCA p 8.8767 62 RCA m 7.9535 70 LCX m 8.9117 69 LAD d6.6648 62 RCA p 8.5454 70 LCX p 8.7533 69 LAD m 6.8614 67 LAD d 8.953270 RCA d 7.3249 69 LAD p 7.7632 67 LAD m 9.2410 70 RCA m 7.1061 70 LAD d7.5175 67 LAD p 8.3841 70 RCA p 8.5830 70 LAD m 7.8630 70 LAD p 8.2222AVG 7.8402 8.5425 7.9475 SD 0.8046 0.8755 0.7349

ActD vs EVOH p = 0.014709 AVG % EEL growth 7.486304

IEL Area (mm2) Actinomycin ID # Control ID # D ID # EVOH 48 LCX d 5.217863 LCX d 6.3785 63 LAD d 6.9687 48 LCX m 6.2108 63 LCX m 7.5206 63 LAD m7.3908 48 LCX p 6.1125 63 LCX p 6.9992 63 LAD p 7.3563 49 LAD d 7.284863 RCA d 6.9632 64 LCX d 6.4420 49 LAD m 7.4117 63 RCA m 6.0418 64 LCX m6.0064 49 LAD p 5.9918 63 RCA p 7.4794 64 LCX p 5.9970 58 LAD d 7.204965 LAD d 6.2324 64 RCA d 6.8001 58 LAD m 6.9334 65 LAD m 8.3785 64 RCA m6.8561 58 LAD p 6.9454 65 LAD p 8.5819 64 RCA p 7.0172 59 LCA d 7.264068 LAD d 8.0964 65 LCX d 5.2485 59 LCX m 6.2014 68 LAD m 8.6879 65 LCX m6.1135 59 LCX p 6.7283 68 LAD p 8.0914 65 RCA d 7.1525 59 RCA d 6.051969 LCX d 8.7181 65 RCA m 6.4815 59 RCA m 5.9992 69 LCX m 8.0273 65 RCA p7.1775 59 RCA p 5.9032 69 LCX p 8.5222 68 LCX d 6.9571 62 LCX d 6.532969 RCA d 8.3796 68 LCX m 6.5724 62 LCX m 6.2804 69 RCA m 6.4219 68 LCX p6.7740 62 LCX p 4.9303 69 RCA p 7.7757 68 RCA d 7.2425 62 RCA d 7.097770 LCX d 7.5392 68 RCA p 7.5554 62 RCA m 6.7466 70 LCX m 7.6573 69 LAD d5.5505 62 RCA p 7.1747 70 LCX p 6.9749 69 LAD m 5.5571 67 LAD d 8.026470 RCA d 6.2815 69 LAD p 6.2697 67 LAD m 8.1144 70 RCA m 5.9760 70 LAD d6.3212 67 LAD p 7.2091 70 RCA p 7.6195 70 LAD m 6.6518 70 LAD p 6.9032AVG 6.6489 7.4727 6.6025 SD 0.7883 0.8972 0.6130

ActD vs EVOH p = 0.000283 AVG % IEL growth 13.17981

FIGS. 10A and 10B illustrate sample pictures of the histology slides ofthe coronary vessels from the control group 64 RCA (Right CoronaryGroup) and the actinomycin D loaded stent group 68 LAD (Left AnteriorDescending), respectively. The stent used was an Advanced CardiovascularSystems Multi-Link Duet™ (stainless steel). As is illustrated by FIG.10B, the positive remodeling of EEL 80, caused by the application ofactinomycin D, creates a gap between stent struts 82 and EEL 80.Thrombus deposits, illustrated by reference number 84, are formed in thegap over time. The use of a self-expandable stent eliminates theformation of the gap as the stent self-expands in response to thepositive remodeling of IEL. Thrombus deposits can be, accordingly,eliminated.

Actinomycin D induces the positive remodeling of the vessel walls, moreparticularly positive remodeling of the external elastic lamina (EEL) ofa blood vessel wall. Positive remodeling is generally defined as theability of the vessel walls to structurally adapt, by increasing inlumen size, to chronic stimuli. A positively remodeled lumen wall has agreater diameter or size as compared to a lumen wall which has not beensubjected to the remodeling effect. Accordingly, the flow of bloodthrough the remodeled site is increased—flow which would have otherwisebeen reduced because of, for example, the presence of plaque build-up ormigration and proliferation of cells. The index of remodeling is definedby the ratio of the area circumscribed by the EEL of the lesion site tothe area circumscribed by the EEL of a reference site. As a result ofthe positive remodeling of the EEL, the internal elastic lamina (IEL),in response, can also increases in area or diameter. Actinomycin D, oranalogs or derivative thereof, not only can inhibit abnormal orinappropriate migration and/or proliferation of smooth muscle cells,which can lead to restenosis, but can also induce positive remodeling ofthe blood vessel walls. Thus the widening of the diseased region becomesmore pronounced.

Example 27

2 grams of an acrylate terminated urethane (Henkel 12892) can be addedto 18 grams of ethyl acetate with 0.08 grams of benzophenone and 0.08grams of 1-hydroxycyclohexyl phenyl ketone. After application, the stentcan be cured for 5 minutes under medium pressure mercury lamp.

Example 28

For a thermoset system, 1.67 grams of Epon 828 (Shell) resin can beadded to 98 grams of propylene glycol monomethyl ether and 0.33 grams ofJeffamine T-430 (Huntsman). After application, the stent can be bakedfor 2 hours at 80 C and 2 hours at 160 C.

Example 29

A 0.25% (w/w) solution of tetra-n-butyl titanate can be made inanhydrous ethyl acetate. The solution can be applied by spraying to asurface of a stainless steel stent. The stent can be heated at 100° C.for two hours.

Example 30 Objective

Coated stents tested through simulated delivery to a target lesion fortesting the mechanical integrity of the coating.

Group Quantity Coating A 2 Control: 2% EVOH in 1:1 THF:DMSO, 3:1EVOH:Act-d; no primer B 2 2% EVOH in 5:3:2 THF:DMF:DMSO, 3:1 EVOH:Act-d; no primer C 2 EVOH primer layer baked at 120 C./60 C. for 2/10hrs + 2% EVOH in 1:1 THF:DMSO, 3:1 EVOH:Act-d; primer D 2 EVOH primerlayer baked at 140 C./60 C. for 2/2 hrs + 2% EVOH in 1:1 THF:DMSO, 3:1EVOH:Act-d; primer

Background

In this experiment four different treatment groups were tested through asimulated delivery and use. Number of peel defects at rings 3, 5, and 7,with a peel defect defined as a location on the stent where coating hasbeen removed to expose bare stent or an underlying layer of coating,were observed.

Materials and Equipment

1. 8, 13 mm Solo stents (Available from Guidant Corporation);

2. 8, 3.0×30 mm Duet catheters;

3. 100% IPA;

4. Tominator Stent Crimper S/N 400;

5. 7F JL4 guiding catheter;

6. 0.014″ Balance Middle Weight guide wire;

7. Rotating Hemostatic Valve;

8. SVS tortuosity tree (2.5 mm lumen tapering to 1.5 mm lumen).

Preparation

Crimped the stents onto the catheters using the Tominator crimper andthe following conditions: 3 crimps, 65 psi, rotation between crimps.

Test Procedure

-   1. Performed simulation using heart model having a tortuosity and    contained in a tub filled with water:    -   a. Inserted the stents through the following set-up: RHF, 7F JL4        guiding catheter, SVS tortuosity tree (2.5 mm lumen at entrance,        1.5 mm lumen at exit).    -   b. Once the stent passed through the distal opening of        tortuosity, the balloon was cut from the catheter just distal to        proximal marker.-   2. Examined the stents under 100× magnification using Leica MZFLIII    microscope in the clean environment room (CER).-   3. Recorded number of peel defects at stent rings 3, 5, and 7. Only    the OD was examined for peel defects.-   4. All test samples were handled with personal protective equipment    (PPE) appropriate for drug containing stents.

Data Summary and Results

Group # Peel Defects/Ring Comments A (THF) 2.0 — B (DMF) 5.3 Began withpoor coating finish. C (140° C.) 0.7 — D (120° C.) 0 —

Discussion

The test was performed to observe the coating integrity after asimulated delivery to a tortuosity without a lesion. The primer layerimproved coating adhesion to the stents that resulted in fewer defectsafter a simulated use. Group B had a number defects. Although thecoating surface for Group B was poor to begin with, and the defects werenot too severe.

Example 31 Objective

The adhesion of 0.67% actinomycin-D (in 5% EVAL 1:1 THF:DMSO solution)coating on stents with two different surface treatments was compared tocontrol samples. The specific surface treatments consisted of: (1) argonplasma treatment; and (2) argon plasma treatment with a primer layer of5% EVOH in 1:1 DMSO:DMF solution applied with the dip-spin process,i.e., centrifugation process, and followed by heat treatments at 120° C.for two hours and 60° C. for 10 hours. The test method used to testadhesion of coatings on stents was a wet flow test, expanding the stentsin a TECOFLEX™ tubing at 37° C. of water or saline. Water or saline isthen flushed through the stents for 18 hours to simulate blood flowthrough the stents. The stents were then removed from the TECOFLEX™ witha “stent catcher” and observed under optical microscope for defects.

Group Treatment Flow Rate A None  50 mL/min B Argon plasma  50 mL/min CArgon plasma + 5% EVOH in 1:1  50 mL/min DMSO:DMF heated at 120° C. fortwo hours and 60° C. for 10 hours D None 100 mL/min E Argon plasma 100mL/min F Argon plasma + 5% EVOH in 1:1 100 mL/min DMSO:DMF heated at120° C. for two hours and 60° C. for 10 hours

Materials and Equipment

-   -   1. 30, 13 mm coated Solo stents, cleaned ultrasonically in IPA        for 15 minutes;    -   2. 30, balloon catheters or subassemblies to expand the stents        (3.0×20 mm RX Rocket);    -   3. 0.67% Actinomycin-D in 5% EVOH with 1:1 THF:DMSO solution;    -   4. 5% EVOH in 1:1 DMF:DMSO;    -   5. 3.0 mm, thin walled TECOFLEX™ tubing;    -   6. Saline;    -   7. Lint Free Wipes SU 00126 or equivalent;    -   8. 100% IPA;    -   9. Oven;    -   10. Timer;    -   11. Centrifuge;    -   12. Plasma Machine (available from Advanced Plasma System);    -   13. Ultrasonic cleaner;    -   14. Mettler balance with 0.1 micrograms resolution; and    -   15. Spray Coater with Fan Air Cap and EFD dispenser (EFD Inc.        East Providence R.I.).

Preparation

1. Sonicated the stents in IPA for 15 minutes;2. Weighed each stent to the nearest microgram;3. Prepared 5 stent samples:

A. Groups A and D:

-   -   i. Performed spray-coating process in CER under the following        conditions: 3 passes, 3-second spray, no blowing.    -   ii. Weighed each sample at the end of the last pass to the        nearest microgram.    -   iii. Baked the samples for 4 hrs at 60° C.    -   iv. Placed the stents into the TECOFLEX™ tubing with a balloon        catheter—submerged in 37° C. saline.

B. Groups B and E:

-   -   i. Placed the samples on a sample holder. Performed argon plasma        treatment using plasma machine.    -   ii. Performed spray-coating process in CER under the following        conditions: 3 passes, 3-second spray, no blow.    -   iii. Weighed each sample at the end of the last pass to the        nearest microgram.    -   iv. Baked the samples for 4 hrs at 60° C.    -   v. Placed the stents into the TECOFLEX™ tubing with the balloon        catheter—submerged in 37° C. saline.

C. Groups C and F:

-   -   i. Placed samples flat on a sample holder. Performed argon        plasma treatment.    -   ii. Used dip-spin process to apply 2% EVOH primer layer, 1:1        DMSO:DMF.    -   iii. Baked the stents at 120° C. for two hours.    -   iv. Baked the stents at 60° C. for ten hours.    -   v. Performed spray-coating process in CER under the following        conditions: 3 passes, 3-second spray, no blow.    -   vi. Weighed each sample at the end of the last pass to the        nearest microgram.    -   vii. Baked the samples for 4 hrs at 60° C.    -   viii. Placed the stents into the TECOFLEX™ tubing with a balloon        catheter—submerged in 37° C. water.

Test Procedure

Tested three samples from each group. Wet Flow Testing:1. Expanded the stents into the 3.0 mm TECOFLEX™ tubing in 37° C.saline.2. Performed wet flow testing for 18 hrs.3. Removed the stents from the TECOFLEX™ tubing with a stent catcher.4. Count defects, based on the following categories: Defect type; defectsize; defect location; and peel defects on rings 3, 5, and 7.5. Stent weight could not be a measurable because of the loss of thedrug and uptake of water.6. All test samples were handled with PPE appropriate for drugcontaining stents.

Data Summary

Average # of Peel Defects/Stent Average # Peel Defects/ Group (3 rings)After Flow Test Ring After Flow Test A 18.0 6.0 B 15.3 5.1 C 2.7 0.9 D14.3 4.8 E 14.0 4.7 F 0.7 0.2

Discussion

Peel defects are defined as areas where the coating separated from thestent. The number of peel defects were counted on the stents'OD/sidewall on rings 3, 5, and 7. The flow field was on the ID of thestents' surface. Some of the damage to the OD surface could have beenaggravated by the TECOFLEX™ tubing. The number of peel defects observedon groups C and F (EVOH primer) was clearly lower than the other twotest groups, regardless of flow rate. The increased flow rate did notinduce more peel defects.

Example 32 Objective

The objective of this experiment was to test the adhesive properties ofan actinomycin-D containing coating on stainless steel stents having anEVOH primer layer. The coated stents were tested in a wet flow testcondition of saline heated to 37° C. The number of “peel defects” on aselect number of stent rings was observed. A “peel defect” is defined asa location on the stent surface devoid of coating, i.e., bare metal orunderlying coating layer that is visible under optical magnification ofless than 100×.

Group Treatment Flow Rate A Argon plasma treatment + EVOH primer layer50 mL/min (15% EVOH, 1:1 DMF:DMSO) baked at 140° C. for 2 hours anddried at 60° C. for 2 hours B Argon plasma treatment + EVOH primer layer50 mL/min (15% EVOH, 1:1 DMF:DMSO) baked at 120° C. for 2 hours anddried at 60° C. for 10 hours

Materials and Equipment

-   -   1. 10, 13 mm Solo stents, cleaned ultrasonically in IPA for 15        minutes;    -   2. 10, balloon catheters or subassemblies to expand the stents;    -   3. 15% EVOH in 1:1 DMF:DMSO solution;    -   4. Actinomycin-D solution, 1:1 THF:DMSO with 3:1 EVOH:Act-D;    -   5. TECOFLEX™ tubing    -   6. Saline    -   7. Lint Free Wipes SU 00126 or equivalent    -   8. 100% IPA    -   9. Oven    -   10. Timer    -   11. Plasma Machine (Advanced Plasma System);    -   12. Ultrasonic cleaner; and    -   13. Mettler balance with 0.1 micrograms resolution.

Preparation

1. Sonicated the stents in IPA for 15 minutes.2. Weighed each stent to the nearest microgram.3. Prepared 5 stent samples for each group:

A. Group A:

-   -   i. Placed the samples flat on a sample holder. Performed argon        plasma treatment.    -   ii. Used dip-spin process, i.e., centrifugation at 6000 rpm for        one minute, to apply the EVOH primer layer, 1:1 DMSO:DMF.    -   iii. Baked the stents at 140° C. for two hours in the convection        oven.    -   iv. Took weight measurements of each stent to the nearest        microgram.    -   v. Baked the stents at 60° C. for two hours in vacuum oven.    -   vi. Took weight measurements of each stent to the nearest        microgram.    -   vii. Performed spray-coating process in CER under the following        conditions: 3 passes, 3-second spray, no blow.    -   viii. Weighed each sample at the end of the last pass to the        nearest microgram.    -   ix. Baked samples for 4 hrs at 60° C.    -   x. Took weight measurements of each stent to the nearest        microgram.    -   xi. Placed the stents into the TECOFLEX™ tubing with a balloon        catheter—submerged in 37° C. water.

B. Groups B:

-   -   i. Placed samples flat on sample holder. Performed argon plasma        treatment.    -   ii. Used dip-spin process at 6000 rpm for one minute to apply        EVOH primer layer, 1:1 DMSO:DMF.    -   iii. Baked the stents at 120° C. for two hours in the convection        oven.    -   iv. Took weight measurements on each stent to the nearest        microgram.    -   v. Baked the stents at 60° C. for ten hours in vacuum oven.    -   vi. Took weight measurements for each stent to the nearest        microgram.    -   vii. Performed spray-coating process in CER at the following        conditions: 3 passes, 3-second spray, no blow.    -   viii. Weighed each sample at the end of the last pass to the        nearest microgram.    -   ix. Baked the samples for 4 hrs at 60° C.    -   x. Took weight measurements of each stent to the nearest        microgram.    -   xi. Placed the stents into the TECOFLEX™ tubing with a balloon        catheter—submerged in 37° C. water.

Test Procedure

-   -   1. Performed wet flow testing overnight for about 18 hrs.    -   2. Removed the stents from the TECOFLEX™ tubing with a stent        catcher.    -   3. Counted the defects based on the number of peel defects at        rings 3, 5, and 7 on the stents' OD. Count the defects on the ID        of the same rings.    -   4. The weight could not be measured because of the loss of the        drug and uptake of water.    -   5. All test samples were handled with PPE appropriate for drug        containing stents.

Data Summary and Results

# Peel Average # of # Peel Average # of Defects Peel Defects/RingDefects Peel Defects/Ring Group (OD) (OD, rings 3, 5, 7) (ID) (ID, rings3, 5, 7) A 0 0 1 0.3 0 0 1 0.3 0 0  1* 0.3 B 0 0 0 0 0 0 0 0 0 0 0 0*Defect occurred at a location of a defect in the stent surface.

Example 33 Objective

The objective of this study was to test the adhesive properties of anactinomycin-D containing coating on stainless steel stents having anEVOH primer layer. The coated stents were tested under wet flowconditions of saline heated to 37° C. The number of “peel defects” on aselect number of stent rings was observed. A “peel defect” is defined asa location on the stent surface devoid of coating, i.e., bare metal oran underlying coating layer that is visible under optical magnificationof no more than 100×.

Group Treatment Flow Rate A None 50 mL/min Control B Argon plasmatreatment + EVOH primer layer 50 mL/min by dip-spin (2% EVOH, 1:1DMF:DMSO) baked at 140° C. for 4 hours C EVOH primer layer by dip-spin(2% EVOH, 1:1 50 mL/min DMF:DMSO) baked at 140° C. for 4 hours D Argonplasma treatment + EVOH primer layer 50 mL/min by spray (2% EVOH, 1:1DMF:DMSO) baked at 140° C. for 4 hours E EVOH primer layer by spray (2%EVOH, 1:1 50 mL/min DMF:DMSO) baked at 140° C. for 4 hours

Materials and Equipment

1. 25, 13 mm Solo stents, cleaned ultrasonically in IPA for 15 minutes;

2. 25, balloon catheters or subassemblies to expand the stents;

3. 2% EVOH in 1:1 DMF:DMSO solution;

4. Actinomycin-D solution, 1:1 THF:DMSO with 3:1 EVOH:Act-D;

5. 3.0 mm TECOFLEX™ tubing;

6. Saline;

7. Lint Free Wipes SU 00126 or equivalent;

8. 100% IPA;

9. Convection Oven

10. Timer;

11. Plasma Machine;

12. Ultrasonic cleaner; and

13. Mettler balance with 0.1 micrograms resolution.

Preparation

1. Sonicated the stents in IPA for 15 minutes.2. Weighed each stent to the nearest microgram.3. Prepared 5 stent samples for each group.

A. Group A (Control):

-   -   i. Performed spray-coating process in CER under the following        conditions: 3 passes, 3-second spray, no blow.    -   ii. Weighed each sample at the end of the last pass to the        nearest microgram.    -   iii. Baked the samples for 4 hrs at 60° C.    -   iv. Took the weight measurements of each stent to the nearest        microgram.    -   v. Placed the stents into the TECOFLEX™ tubing with the balloon        catheter—submerged in 37° C. water.

B. Group B:

-   -   i. Placed samples flat on sample holder. Performed argon plasma        treatment.    -   ii. Used dip-spin process to apply EVOH primer layer, 1:1        DMSO:DMF (6000 rpm for one minute).    -   iii. Baked the stents at 140° C. for 4 hours in convection oven.    -   iv. Took weight measurements on each stent to the nearest        microgram.    -   v. Performed spray-coating process in CER at the following        conditions: 3 passes, 3-second spray, no blow.    -   vi. Weighed each sample at the end of the last pass to the        nearest microgram.    -   vii. Baked the samples for 4 hrs at 60° C.    -   viii. Took the weight measurements of each stent to the nearest        microgram.    -   ix. Placed the stents into the TECOFLEX™ tubing with a balloon        catheter—submerged in 37° C. water.

C. Group C:

-   -   i. Used dip-spin process to apply EVOH primer layer, 1:1        DMSO:DMF (6000 rpm for one minute).    -   ii. Baked the stents at 140° C. for four hours in convection        oven.    -   iii. Took weight measurements on each stent to the nearest        microgram.    -   iv. Performed spray-coating process in CER under the following        conditions: 3 passes, 3-second spray, no blow.    -   v. Weighed each sample at the end of the last pass to the        nearest microgram.    -   vi. Baked the samples for 4 hrs at 60° C.    -   vii. Took weight measurements of each stent to the nearest        microgram.    -   viii. Placed stents into the TECOFLEX™ tubing with a balloon        catheter—submerged in 37° C. water.

D. Group D:

-   -   i. Placed the samples flat on a sample holder. Perform argon        plasma treatment.    -   ii. Spray coated primer layer (2% EVOH, 1:1 DMF:DMSO) onto the        stents. Used 1.5 sec. spray time, 1-2 passes to achieve 10-40        micrograms of coating.    -   iii. Baked the stents at 140° C. for 4 hours in the convection        oven.    -   iv. Took weight measurements on each stent to the nearest        microgram.    -   v. Performed spray-coating process in CER at the following        conditions: 3 passes, 3-second spray, no blow.    -   vi. Weighed each sample at the end of the last pass to the        nearest microgram.    -   vii. Baked samples for 4 hrs at 60° C.    -   viii. Took weight measurements of each stent to the nearest        microgram.    -   ix. Placed stents into the TECOFLEX™ tubing with a balloon        catheter—submerged in 37° C. water.

E. Group E:

-   -   i. Spray coated primer layer (2% EVOH, 1:1 DMF:DMSO) onto the        stents. Used 1.5 sec. spray time, 1-2 passes to achieve 10-40        micrograms of coating.    -   ii. Baked the stents at 140° C. for four hours in convection        oven.    -   iii. Took weight measurements on each stent to the nearest        microgram.    -   iv. Performed spray-coating process in CER at the following        conditions: 3 passes, 3-second spray, no blow.    -   v. Weighed each sample at the end of the last pass to the        nearest microgram.    -   vi. Baked the samples for 4 hrs at 60° C.    -   vii. Took weight measurements of each stent to the nearest        microgram.    -   viii. Placed the stents into the TECOFLEX™ tubing with a balloon        catheter—submerged in 37° C. water.

Test Procedure

-   -   1. Performed wet flow testing overnight for about 18 hrs.    -   2. Removed stents from the TECOFLEX™ tubing with a stent        catcher.    -   3. Counted the defects based on the number of peel defects at        rings 1, 3, 5, and 7 on the stents' OD. Count the defects on the        ID of the same rings.    -   4. Stent weight could not be a measurable because of the loss of        the drug and uptake of water.    -   5. All test samples were handled with PPE appropriate for drug        containing stents.

Data Summary and Results

Group Defects/Ring (OD) Defects/Ring (ID) Control 2.67 3.00 Dip/Plasma0.67 0.47 Dip/No Plasma 0.87 0.80 Spray/Plasma 0.47 0.80 Spray/No Plasma0.67 0.73

Discussion

Peel Defects of Primer Coated Stents vs. Untreated Controls

An improved adhesion, based on the number of peel defects, of the drugcontaining coating to the Tri-Star stent when an EVOH primer layer wasapplied is illustrated. All four treatment groups displayedsignificantly fewer peel defects per stent than the untreated controlstents. Use of a spray-coated, 2% EVOH solution in 1:1 DMF:DMSO as aprimer significantly improved adhesion of actinomycin-D containingcoating to the Tri-Star stents vs. the controls. The spray-coated primerproduced slightly higher peel defect counts compared to the dip-spindeposited primer.

Example 34 Objective

The objective of this experiment was to test the adhesive properties ofan Actinomycin-D containing coating to stainless steel stents having anEVOH primer layer. More specifically, this experiment attempted toillustrate the effect of different bake times on the final result. Thecoated stents were tested under wet flow conditions of saline heated to37° C. The number of “peel defects” on a select number of stent ringswas observed.

Group Treatment Flow Rate A none 50 mL/min Control B Argon plasmatreatment + EVOH primer layer 50 mL/min by spray (2% EVOH, 1:1 DMF:DMSO)baked at 140° C. for 15 minutes C Argon plasma treatment + EVOH primerlayer 50 mL/min by spray (2% EVOH, 1:1 DMF:DMSO) baked at 140° C. for 30minutes D Argon plasma treatment + EVOH primer layer 50 mL/min by spray(2% EVOH, 1:1 DMF:DMSO) baked at 140° C. for 60 minutes E Argon plasmatreatment + EVOH primer layer 50 mL/min by spray (2% EVOH, 1:1 DMF:DMSO)baked at 140° C. for 120 minutes

Materials and Equipment

1. 25, 13 mm Solo stents, cleaned ultrasonically in IPA for 15 minutes;

2. 25, balloon catheters or subassemblies to expand the stents;

3. 2% EVOH in 1:1 DMF:DMSO solution;

4. Actinomycin-D solution, 1:1 THF:DMSO with 3:1 EVOH:Act-D;

5. 3.0 mm TECOFLEX™ tubing;

6. Saline;

7. Lint Free Wipes SU 00126 or equivalent;

8. 100% IPA;

9. Convection Oven;

10. Timer;

11. Plasma Machine;

12. Ultrasonic cleaner; and

13. Mettler balance with 0.1 micrograms resolution.

Preparation

1. Sonicated stents in IPA for 15 minutes.2. Weighed each stent to the nearest microgram.3. Prepared 5 stent samples for each group.

A. Group A (Control):

-   -   i. Performed spray-coating process in CER under the following        conditions: 3 passes, 3-second spray, no blow.    -   ii. Weighed each sample at the end of the last pass to the        nearest microgram.    -   iii. Baked the samples for 240 minutes at 50° C.    -   iv. Took weight measurements of each stent to the nearest        microgram.    -   v. Placed the stents into the TECOFLEX™ tubing with a balloon        catheter—submerged in 37° C. water.

B. Group B:

-   -   i. Placed samples flat on sample holder. Perform argon plasma        treatment.    -   ii. Spray coated primer layer (2% EVOH, 1:1 DMF:DMSO) onto        stents. Used 1.5 sec. spray time, 1-2 passes to achieve 10-40        micrograms of coating.    -   iii. Baked the stents at 140° C. for 15 minutes in the        convection oven.    -   iv. Took weight measurements on each stent to the nearest        microgram.    -   v. Performed spray-coating process in CER under the following        conditions: 3 passes, 3-second spray, no blow.    -   vi. Weighed each sample at the end of the last pass to the        nearest microgram.    -   vii. Baked the samples for 240 minutes at 50° C.    -   viii. Took weight measurements of each stent to the nearest        microgram.    -   ix. Placed stents into the TECOFLEX™ tubing with a balloon        catheter—submerged in 37° C. water.

C. Group C:

-   -   i. Placed the samples flat on sample holder. Perform argon        plasma treatment.    -   ii. Spray coated primer layer (2% EVOH, 1:1 DMF:DMSO) onto        stents. Used 1.5 sec. spray time, 1-2 passes to achieve 10-40        micrograms of coating.    -   iii. Baked the stents at 140° C. for 30 minutes in the        convection oven.    -   iv. Took weight measurements on each stent to the nearest        microgram.    -   v. Performed spray-coating process in CER under the following        conditions: 3 passes, 3-second spray, no blow.    -   vi. Weighed each sample at the end of the last pass to the        nearest microgram.    -   vii. Baked the samples for 240 minutes at 50° C.    -   viii. Took weight measurements of each stent to the nearest        microgram.    -   ix. Placed stents into the TECOFLEX™ tubing with a balloon        catheter—submerged in 37° C. water.

D. Group D:

-   -   i. Placed samples flat on sample holder. Perform argon plasma        treatment.    -   ii. Spray coated primer layer (2% EVOH, 1:1 DMF:DMSO) onto        stents. Used 1.5 sec. spray time, 1-2 passes to achieve 10-40        micrograms of coating.    -   iii. Baked the stents at 140° C. for 60 minutes in the        convection oven.    -   iv. Took weight measurements on each stent to the nearest        microgram.    -   v. Performed spray-coating process in CER under the following        conditions: 3 passes, 3-second spray, no blow.    -   vi. Weighed each sample at the end of the last pass to the        nearest microgram.    -   vii. Baked the samples for 240 minutes at 50° C.    -   viii. Took weight measurements of each stent to the nearest        microgram.    -   ix. Placed stents into the TECOFLEX™ tubing with a balloon        catheter—submerged in 37° C. water.

E. Group E:

-   -   i. Placed samples flat on sample holder. Perform argon plasma        treatment.    -   ii. Spray coated primer layer (2% EVOH, 1:1 DMF:DMSO) onto        stents. Used 1.5 sec. spray time, 1-2 passes to achieve 10-40        micrograms of coating.    -   iii. Baked the stents at 140° C. for 120 minutes in the        convection oven.    -   iv. Took weight measurements on each stent to the nearest        microgram.    -   v. Performed spray-coating process in CER at the following        conditions: 3 passes, 3-second spray, no blow.    -   vi. Weighed each sample at the end of the last pass to the        nearest microgram.    -   vii. Baked samples for 240 minutes at 50° C.    -   viii. Took weight measurements of each stent to the nearest        microgram.    -   ix. Placed stent into the TECOFLEX™ tube with balloon        catheter—submerged in 37° C. water.

Test Procedure

-   -   1. Performed wet flow testing overnight for about 18 hrs.    -   2. Removed the stents from the TECOFLEX™ tubing with a stent        catcher.    -   3. Counted the defects based on the number of peel defects at        rings 3, 5, and 7 on the stents' OD. Count the defects on the ID        of the same rings.    -   4. Stent weight could not be a measurable because of the loss of        the drug and uptake of water.    -   5. All test samples were handled with PPE appropriate for drug        containing stents.

Data Summary and Results

Group Total Defects per Stent Control 3.33 15 min bake 1.00 30 min bake3.00 60 min bake 1.67 120 min bake  1.33

Discussion

The control group with no primer layer had significantly more peeldefects as compared to the treatment groups with a primer layer. Thegroups with shorter baking times (15 and 30 minutes) had higher defectcounts than the groups with longer baking times.

Example 35 Objective

The objective of this experiment was to test the adhesive properties ofan actinomycin-D containing coating on stainless steel stents having anEVOH primer layer. More specifically, different solvent systems (e.g.,THF and DMF) were evaluated. The coated stents were tested under wetflow conditions of saline heated to 37° C. The number of “peel defects”on a select number of stent rings was observed.

Group Treatment Flow Rate A none 50 mL/min Control B Argon plasmatreatment + EVOH primer layer 50 mL/min by spray (2% EVOH, 1:1 DMF:DMSO)baked at 140° C. for 15 minutes C Argon plasma treatment + EVOH primerlayer 50 mL/min by spray (2% EVOH, 1:1 DMF:DMSO) baked at 140° C. for 60minutes D Argon plasma treatment + EVOH primer layer 50 mL/min by spray(2% EVOH, 1:1 DMF:DMSO) baked at 140° C. for 240 minutes E Argon plasmatreatment + EVOH primer layer 50 mL/min by spray (2% EVOH, 1:1 THF:DMSO)baked at 140° C. for 60 minutes

Materials and Equipment

-   -   1. 25, 13 mm Solo stents, cleaned ultrasonically in IPA for 15        minutes;    -   2. 25, balloon catheters or subassemblies to expand the stents;    -   3. 2% EVOH in 1:1 DMF:DMSO solution;    -   4. 2% EVOH in 1:1 THF:DMSO solution;    -   5. Actinomycin-D solution, 1:1 THF:DMSO with 3:1 EVOH:Act-D, 2%        EVOH;    -   6. 3.0 mm TECOFLEX™ tubing;    -   7. Saline;    -   8. Lint Free Wipes SU 00126 or equivalent;    -   9. 100% IPA;    -   10. Convection Oven;    -   11. Timer;    -   12. Plasma Machine;    -   13. Ultrasonic cleaner; and    -   14. Mettler balance with 0.1 micrograms resolution.

Preparation

1. Sonicated stents in IPA for 15 minutes.2. Weighed each stent to the nearest microgram.3. Prepared 5 stent samples for each group.

A. Group A (Control):

-   -   i. Performed spray-coating process in CER under the following        conditions: 3 passes, 3-second spray, no blow.    -   ii. Weighed each sample at the end of the last pass to the        nearest microgram.    -   iii. Baked samples for 240 minutes at 50° C.    -   iv. Took weight measurements of each stent to the nearest        microgram.    -   v. Placed the stents into the TECOFLEX™ tubing with a balloon        catheter—submerged in 37° C. water.

B. Group B:

-   -   i. Placed samples flat on a sample holder. Performed argon        plasma treatment.    -   ii. Spray coated the primer layer (2% EVOH, 1:1 DMF: DMSO) onto        the stents. Used 1.5 sec. spray time, 1-2 passes to achieve        10-40 micrograms of coating.    -   iii. Baked the stents at 140° C. for 15 minutes in the        convection oven.    -   iv. Took weight measurements of each stent to the nearest        microgram.    -   v. Performed spray-coating process in CER under the following        conditions: 3 passes, 3-second spray, no blow.    -   vi. Weighed each sample at the end of the last pass to the        nearest microgram.    -   vii. Baked the samples for 240 minutes at 50° C.    -   viii. Took weight measurements of each stent to the nearest        microgram.    -   ix. Placed the stents into the TECOFLEX™ tubing with a balloon        catheter—submerged in 37° C. water.

C. Group C:

-   -   i. Placed samples flat on a sample holder. Performed argon        plasma treatment.    -   ii. Spray coated the primer layer (2% EVOH, 1:1 DMF: DMSO) onto        the stents. Used 1.5 sec. spray time, 1-2 passes to achieve        10-40 micrograms of coating.    -   iii. Baked the stents at 140° C. for 60 minutes in the        convection oven.    -   iv. Took weight measurements of each stent to the nearest        microgram.    -   v. Performed spray-coating process in CER under the following        conditions: 3 passes, 3-second spray, no blow.    -   vi. Weighed each sample at the end of the last pass to the        nearest microgram.    -   vii. Baked the samples for 240 minutes at 50° C.    -   viii. Took weight measurements of each stent to the nearest        microgram.    -   ix. Placed the stents into the TECOFLEX™ tubing with a balloon        catheter—submerged in 37° C. water.

D. Group D:

-   -   i. Placed samples on flat on a sample holder. Performed argon        plasma treatment.    -   ii. Spray coated the primer layer (2% EVOH, 1:1 DMF: DMSO) onto        the stents. Used 1.5 sec. spray time, 1-2 passes to achieve        10-40 micrograms of coating.    -   iii. Baked the stents at 140° C. for 240 minutes in the        convection oven.    -   iv. Took weight measurements of each stent to the nearest        microgram.    -   v. Performed spray-coating process in CER at the following        conditions: 3 passes, 3-second spray, no blow.    -   vi. Weighed each sample at the end of the last pass to the        nearest microgram.    -   vii. Baked the samples for 240 minutes at 50° C.    -   viii. Took weight measurements of each stent to the nearest        microgram.    -   ix. Placed the stents into the TECOFLEX™ tubing with a balloon        catheter—submerged in 37° C. water.

E. Group E:

-   -   i. Placed samples flat on a sample holder. Perform argon plasma        treatment.    -   ii. Spray coated the primer layer (2% EVOH, 1:1 THF:DMSO) onto        the stents. Used 1.5 sec. spray time, 1-2 passes to achieve        10-40 micrograms of coating.    -   iii. Baked the stents at 140° C. for 60 minutes in the        convection oven.    -   iv. Took weight measurements of each stent to the nearest        microgram.    -   v. Performed spray-coating process in CER under the following        conditions: 3 passes, 3 second spray, no blow.    -   vi. Weighed each sample at the end of the last pass to the        nearest microgram.    -   vii. Baked the samples for 240 minutes at 50° C.    -   viii. Took weight measurements of each stent to the nearest        microgram.    -   ix. Placed the stents into the TECOFLEX™ tubing with a balloon        catheter—submerged in 37° C. water.

Test Procedure

-   -   1. Performed wet flow testing overnight for about 18 hrs.    -   2. Removed the stents from the TECOFLEX™ tubing with a stent        catcher.    -   3. Counted the defects, based on the number of peel defects at        rings 3, 5, and 7 on the stents' OD. Counted defects on the ID        of the same rings.    -   4. The weight of the stents could not be a measurable because of        the loss of the drug and uptake of water.    -   5. All test samples were handled with PPE appropriate for drug        containing stents.

Data Summary and Results

Group Total Defects per Stent No primer control 0.00 15 min. bake 0.0060 min. bake 0.33 240 min. bake  0.00 THF, 15 min. bake 0.00

Example 36 Objective

The objective of this experiment was to test the adhesive properties ofan actinomycin-D containing coating on stainless steel stents having anEVOH primer layer made from a DMSO:THF solution applied to the stents.The coated stents were tested under wet flow conditions of saline heatedto 37° C. The number of “peel defects” on a select number of stent ringswas observed.

Drying Time Group Treatment (min.) A Argon plasma treatment + EVOHprimer layer 15 B Argon plasma treatment + EVOH primer layer 30 C Argonplasma treatment + EVOH primer layer 60 D Argon plasma treatment + EVOHprimer layer 90 E Argon plasma treatment + EVOH primer layer 120

Materials and Equipment

-   -   1. 10, 13 mm SOLO stents, cleaned ultrasonically in IPA for 15        minutes;    -   2.2% EVOH in 1:1 THF:DMSO solution;    -   3. 10 Balloon catheters or subassemblies to expand the stents;    -   4. Actinomycin-D solution, 1:1 THF:DMSO with 1:3 Act-D:EVOH, 2%        EVOH;    -   5. 4.0 mm TECOFLEX™ tubing;    -   6. Saline;    -   7. Lint Free Wipes SU 00126 or equivalent;    -   8. 100% IPA;    -   9. Convection Oven;    -   10. Timer;    -   11. Plasma Machine;    -   12. Ultrasonic cleaner;    -   13. Mettler balance with 0.1 microgram resolution;    -   14. Spray/bake mandrels and tips;    -   15. Flow Meter, N1429;    -   16. Microscope, minimum magnification 50×;    -   17. EFD controller with spray apparatus without translational        stage; and    -   18. EFD controller with spray apparatus with translational        stage.

Preparation

1. Sonicated the stents in IPA for 15 minutes.2. Weighed each stent to the nearest microgram.3. Prepare the stent samples for each group.

A. Primer Coat

-   -   i. Placed samples on sample holder. Performed argon plasma        treatment.    -   ii. Sprayed the primer layer (2% EVOH, 1:1 THF:DMSO) onto the        stents with translational spray coater. Used 1.5 sec. for the        spray time and speed 7 to achieve 10-40 μg of coating.    -   iii. Baked the stents at 140° C. for the specified time in the        convection oven.    -   iv. Weighed the stents and recorded measurements to the nearest        microgram.

B. Drug Coat

-   -   i. Sprayed the stents with a 3:1, EVOH:Act-D, 2% EVOH, 1:1        DMSO:THF solution for three seconds per pass for three passes.        After each spray pass, dried the stents in the convection oven        for 15 minutes at 50° C.    -   ii. Weighed the stents and recorded measurements. If the drug        coat weight matched the target weight, the stents were returned        to the oven for 240 minutes. If weight gain did not match, the        stents were returned to the glove box for additional spray coat        application. Spray time on subsequent passes was adjusted to        achieve target weight.

4. Wet Flow Test Sample Preparation

-   -   A. Crimped the stents onto the balloon catheters.    -   B. Inflated the stents to 4.0 mm in the TECOFLEX™ tubing with        the balloon catheters—submerged in 37° C. water.    -   C. Disposed Act-D contaminated water as hazardous waste.

Test Method/Procedure

1. Set flow rate at 50 ml/min.2. Performed wet flow testing overnight for about 18 hrs.3. Removed the stents from the TECOFLEX™ tubing with a stent catcher.4. Counted defects, based on the number of peel defects at rings 1, 3,5, 7, and 10 on the stents' OD. Counted defects on the ID of the samerings.5. All test samples were handled with PPE appropriate for drugcontaining stents.

Data Summary and Results

Drying Total Defects Total Defects per Total Defects per Time (min.) perStent Stent (end rings) Stent (middle rings) 15 0.0 0.0 0.0 30 2.0 2.00.0 60 1.0 1.0 0.0 90 0.0 0.0 0.0 120 0.5 0.5 0.0

Example 37

Thirty-five (35) 13 mm PENTA stents (available from Guidant Corporation)were coated by spraying a 2% (w/w) solution of EVOH (44 mole % ethylene)in 98% (w/w) dimethylacetamide. The solvent was removed by baking at140° C. for 2 hours. A solution of 1.9% (w/w) EVOH and 0.7% (w/w)40-O-(2-hydroxy)ethyl-rapamycin in a mixture of 68.2% (w/w)dimethylacetamide and 29.2% (w/w) ethanol was spray coated onto thestents to a thickness with a target of 175 μg of40-O-(2-hydroxy)ethyl-rapamycin on each stent. The stents were thenbaked at 50° C. for 2 hours. A barrier layer was formed by spraying thestents with a 4% (w/w) solution of EVOH in a mixture of 76% (w/w)dimethylacetamide and 20% (w/w) pentane. Another 2 hour bake at 50° C.was performed to remove the solvent.

A select number of stents were analyzed to compare the target coatingformulation with the final coating formulation. The results are asfollows: For the primer layer, there was a target dry weight of 40 μg ofpolymer, and a measured average dry weight of 43±3 μg of polymer. Forthe reservoir layer, the target drug:polymer ratio was 1:2.857, thetarget dry weight for the entire reservoir coating was 675 μg and theaverage actual dry weight was 683±19 μg. Also for the reservoir layer,the average total drug content of the stent coatings was determined bythe process described in Example 38. The average drug content was 133 μgor 152 μg/cm². For the barrier layer, the target dry weight of polymerwas 300 μg and the measured average dry weight was 320±13 μg.

Example 38

A drug-coated stent was placed in a volumetric flask. An appropriateamount of the extraction solvent acetonitrile with 0.02% BHT asprotectant was added (e.g., in a 10 ml volumetric flask, with about 9 mlsolvent added). The flask was sonicated for a sufficient time to extractall of the drug from the reservoir region. Then, the solution in theflask was filled to mark with the solvent solution. The drug solutionwas the analyzed by HPLC. The HPLC system consisted of a Waters 2690system with an analytical pump, a column compartment (set at 40° C.), anauto-sampler, and a 996 PDA detector. The column was an YMC Pro C18 (150mm×4.6 I.D., 3 μm particle size), maintained at a temperature of 40° C.The mobile phase consisted of 75% acetonitrile and 25% 20 mMolarammonium acetate. The flow rate was set on 1 ml/min. The HPLC releaserate results were quantified by comparing the results with a referencestandard. The total drug content of the stent was then calculated.

Example 39

Thirty-four (34) 13 mm PENTA stents were coated by spraying a 2% (w/w)solution of EVOH and 98% (w/w) dimethylacetamide. The solvent wasremoved by baking at 140° C. for 2 hours. A solution of 1.9% (w/w) EVOHand 1.1% (w/w) 40-O-(2-hydroxy)ethyl-rapamycin in a mixture of 67.9%(w/w) dimethylacetamide and 29.1% (w/w) ethanol was spray coated ontothe stents to a thickness with a target of 275 μg of40-O-(2-hydroxy)ethyl-rapamycin on each stent. The stents were thenbaked at 50° C. for 2 hours. A barrier layer was formed by spraying thestents with a 4% (w/w) solution of EVOH in a mixture of 76% (w/w)dimethylacetamide and 20% (w/w) pentane. Another 2 hour bake at 50° C.was performed to remove the solvent.

A select number of stents were analyzed to compare the target coatingformulation with the final coating formulation. The results are asfollows: For the primer layer, there was a target dry weight of 40 μg ofpolymer, and a measured average dry weight of 43±3 μg of polymer. Forthe reservoir layer, the target drug:polymer ratio was 1:1.75, thetarget dry weight for the entire reservoir coating was 757 μg and theaverage actual dry weight was 752±23 μg. Also for the reservoir layer,the average total drug content of the stent coatings was determined bythe process described in Example 38. The average drug content was 205 μgor 235 μg/cm². For the barrier layer, the target dry weight of polymerwas 200 μg and the measured average dry weight was 186±13 μg.

Example 40

Twenty-four (24) 13 mm PENTA stents were coated by spraying a 2% (w/w)solution of EVOH and 98% (w/w) dimethylacetamide. The solvent wasremoved by baking at 140° C. for 2 hours. A solution of 1.9% (w/w) EVOHand 1.2% (w/w) 40-O-(2-hydroxy)ethyl-rapamycin in a mixture of 67.8%(w/w) dimethylacetamide and 29.1% (w/w) ethanol was spray coated ontothe stents to a thickness with a target of 325 μg of40-O-(2-hydroxy)ethyl-rapamycin on each stent. The stents were thenbaked at 50° C. for 2 hours. A barrier layer was formed by spraying thestents with a 4% (w/w) solution of EVOH in a mixture of 76% (w/w)dimethylacetamide and 20% (w/w) pentane. Another 2 hour bake at 50° C.was performed to remove the solvent.

A select number of stents were analyzed to compare the target coatingformulation with the final coating formulation. The results are asfollows: For the primer layer, there was a target dry weight of 40 μg ofpolymer, and a measured average dry weight of 41±2 μg of polymer. Forthe reservoir layer, the target drug:polymer ratio was 1:1.6, the targetdry weight for the entire reservoir coating was 845 μg and the averageactual dry weight was 861±16 μg. Also for the reservoir layer, theaverage total drug content of the stent coatings was determined by theprocess described in Example 38. The average drug content was 282 μg or323 μg/cm². For the barrier layer, the target dry weight of polymer was125 μg and the measured average dry weight was 131±9 μg.

Example 41

This Example 41 is referred to as the “Release Rate Profile Procedure.”A drug-coated stent was placed on a stent holder of a Vankel Bio-Disrelease rate tester (Vankel, Inc., Cary, N.C.). The stent was dippedinto an artificial medium which stabilizes the40-O-(2-hydroxy)ethyl-rapamycin in the testing solution, including aphosphate buffer saline solution (10 mM, pH 7.4) with 1% TRITON X-100(Sigma Corporation), for a designated amount of time (e.g., 3 hours).Then the solution was analyzed for the amount of drug released from thestent coating using an HPLC process. The HPLC system consisted of aWaters 2690 system with an analytical pump, a column compartment (set at40° C.), an auto-sampler, and a 996 PDA detector. The column was an YMCPro C18 (150 mm×4.6 I.D., 3 μm particle size), maintained at atemperature of 40° C. The mobile phase consisted of 75% acetonitrile and25% 20 mMolar ammonium acetate. The flow rate was set on 1 ml/min. Afterthe drug solution was analyzed by HPLC the results were quantified bycomparing the release rate results with a reference standard.

If the experimental protocol required that the stent coating besubjected to experimental conditions for an additional time, the stentwas then dipped in a fresh medium solution for the necessary amount oftime (e.g., another 3 hours) and the drug released in the solution wasanalyzed again according to the HPLC procedure described above. Theprocedure was repeated according to the number of data points required.The release rate profile could then be generated by plotting cumulativedrug released in the medium vs. time.

Example 42

The release rate of 40-O-(2-hydroxy)ethyl-rapamycin from the stents withcoatings produced by the processes under Examples 37, 39 and 40 weretested using the in vitro HPLC process as described in Example 41. Thesolution for each stent underwent two HPLC runs, and the results wereaveraged.

The following Table 7 summarizes the results of the release rateprocedure for two stents from Example 37:

TABLE 7 Time (hrs) 3 6 9 12 23 32 48 Cumulative Release 3.72 5.62 7.128.43 12.28 15.31 20.28 from Stent 1 (μg) Cumulative Release 4.18 6.538.54 10.29 15.64 19.66 26.3 from Stent 2 (μg)

The following Table 8 summarizes the results of the release rateprocedure for two stents from Example 39:

TABLE 8 Time (hrs) 3 6 9 12 23 32 48 Cumulative Release 29.73 45.3557.79 68.19 95.2 110.85 130.75 from Stent 1 (μg) Cumulative Release26.36 41.2 53.5 63.99 93.93 112.31 135.7 from Stent 2 (μg)

The following Table 9 summarizes the results of the release rateprocedure for two stents from Example 40:

TABLE 9 Time (hrs) 3 6 9 12 23 32 48 Cumulative Release 46.24 67.4 82.7994.92 124.72 141.96 165.12 from Stent 1 (μg) Cumulative Release 44.6666.74 82.26 94.49 123.92 140.07 159.65 from Stent 2 (μg)

A comparison of the release rates for the stents from Examples 37, 39and 40 is graphically shown in FIG. 11.

Example 43

The following Example 43 is referred to as the “3 day In Vivo ReleaseRate Procedure” or the “9 day In Vivo Release Rate Procedure,” dependingon the number of days the stents are inserted into the experimentalanimal. The following are the materials used for this Example:

1. Experimental animal: One 30-45 kg Yorkshire cross pig;

2. BMW™ wires 0.014″, 190 cm;

3. Guide wire 0.035″, 190 cm;

4. Viking guide catheters, 7F;

5. Introducer sheaths (8-10F);

6. ACS 20/20 Indeflator™ Inflation Device;

7. Saline; solution with heparin;

8. Nitroglycerin, Lidocaine, other inotropic/chronotropic drugs;

9. Standard surgical equipment, anesthetic, and medications asnecessary;

10. Respiratory and hemodynamic monitoring systems;

11. Positive pressure ventilator and associated breathing circuits;

12. ACT machine and accessories;

13. PTCA accessories;

14. Ambulatory defibrillator;

15. Fluoroscopy equipment; and

16. Non-ionic contrast agent.

The following was the procedure used for this Example:

A. Animal Preparation.

-   -   1. Administer Aspirin (325 mg PO) once daily starting one day        prior to stent implantation.    -   2. Sedate the pig.    -   3. Intubate the trachea via an oral approach.    -   4. Deliver isoflurane (up to about 5%) to achieve and maintain        an adequate plane of anesthesia.    -   5. Shave the sheath introduction area free of hair and scrub the        surgical site with surgical soap and/or antiseptic solution.    -   6. Place a 7F introducer sheath into the right or left femoral        artery.    -   7. Obtain an arterial blood sample for a baseline ACT.    -   8. Administer heparin 200 units/kg IV (not to exceed 100,000        units) and obtain a blood sample for measurement of ACT 5-10        minutes later.    -   9. Repeat heparin as needed to maintain ACT≧300 seconds.    -   10. Measure and record arterial blood pressure, heart rate and        electrocardiogram (ECG).        B. Angiography for vessel selection.    -   1. Advance the guiding catheter over the guidewire into the        aortic arch and cannulate the desired vessel.    -   2. Administer nitroglycerin (200 μg) intra-luminally prior to        baseline angiography.    -   3. Perform baseline angiogram and record images on cine.    -   4. With the diameter of the guiding catheter as a reference,        select vasculature that will allow a target stent to artery        ratio of about 1.1:1.0.

C. Stent Preparation and Deployment.

-   -   1. Perform online QCA and measure baseline proximal, target, and        distal reference sites.    -   2. Administer nitroglycerin (200 μg) intra-luminally prior to        stent deployment, then as needed to control coronary artery        vasospasm.    -   3. Inspect the stent delivery system. Ensure that the stent is        correctly positioned on the balloon. Inspect the stent for any        abnormalities.    -   4. Flush guidewire lumen with heparinized saline until fluid        exits the guidewire notch.    -   5. Prepare Indeflator/syringe with diluted (approximately 50:50)        contrast medium.    -   6. Attach syringe to test catheter inflation port; use standard        techniques to fill the inflation lumen with diluted contrast.    -   7. Purge syringe and test catheter inflation lumen of all air.    -   8. Purge Indeflator of all air and attach to test catheter        inflation port.    -   9. Position an appropriate guidewire in the distal bed of the        target artery.    -   10. Insert the stent delivery system through the guiding        catheter over the guidewire.    -   11. Advance the stent delivery system to the pre-selected        arterial deployment site.    -   12. Position balloon for inflation.    -   13. Refer to IFU for inflation strategy. If no IFU available,        inflate the balloon at a slow steady rate to a pressure that        expands the stent to the desired diameter. Hold at this pressure        for 30 seconds.    -   14. Record inflated balloon by pulling image on cine. Perform        on-line QCA and measure the inflated balloon diameter.    -   15. Deflate balloon by pulling negative pressure. While        withdrawing the system, observe tactually and fluoroscopically.        Record any resistance.    -   16. Administer nitroglycerin (200 μg) intra-luminally.    -   17. Assess patency, deployment, and placement of stent via        coronary angiography.    -   18. Assess TIMI angiographic low grade.    -   19. Record on cine and video.    -   20. Measure post-proximal, target, and distal MLD with QCA.    -   21. Repeat Section C with remaining stent delivery system.    -   22. Measure and record heart rate, arterial blood pressure and        electrocardiogram (ECG).

D. Stent Procedure End.

-   -   1. Remove the guidewire, guiding catheter and introducer sheath.    -   2. Remove introducer sheath from the femoral artery.    -   3. Apply pressure to the femoral artery at the side of sheath        entry.    -   4. Allow the animal to recover from anesthesia in an individual        cage.    -   5. Give Buprenorphine (0.05 mg/kg) PRN as needed for pain.    -   6. Administer Ticlopidine (250 mg PO) and aspirin (325 mg PO)        once daily until date of follow-up angiography.

E. Study End.

-   -   1. Euthanize the pig with an overdose of barbiturates and/or        potassium chloride.    -   2. Excise the heart without flushing the vessels.    -   3. Harvest all stented arteries.    -   4. Remove the stent from all treated arteries and place them in        dark colored amber vials for subsequent drug concentration        analysis.    -   5. Snap freeze the arterial tissue in liquid nitrogen and store        at −70° C. until subsequent analysis of tissue for drug        concentrations as determined by HPLC.

The stents harvested from the experimental animals were tested using anHPLC procedure to determine how much drug remained on the stents. Adrug-coated stent removed from the experimental animal was placed in avolumetric flask. An appropriate amount of the extraction solventacetonitrile with 0.02% BHT as protectant was added (e.g., in a 10 mlvolumetric flask, with about 9 ml solvent added). The flask wassonicated for a sufficient time to extract all of the drug from thereservoir region. Then, the solution in the flask was filled to markwith the solvent solution. The HPLC system consisted of a Waters 2690system with an analytical pump, a column compartment (set at 40° C.), anauto-sampler, and a 996 PDA detector. The column was an YMC Pro C18 (150mm×4.6 I.D., 3 μm particle size), maintained at a temperature of 40° C.The mobile phase consisted of 75% acetonitrile and 25% 20 mMolarammonium acetate. The flow rate was set on 1 ml/min. The HPLC releaserate results were quantified by comparing the results with a referencestandard. The total drug released in vivo was the difference between theaverage drug loaded on the stents and the amount of drug remaining onthe stents after the stent implantation into the experimental animal.

Example 44

The release rate of 40-O-(2-hydroxy)ethyl-rapamycin from the stents withcoatings produced by the process under Example 37 were tested using a 3day in vivo process as described in Example 43. In particular, stentsfrom Example 37 were implanted into experimental animals and then thestents were tested by HPLC to determine how much40-O-(2-hydroxy)ethyl-rapamycin diffused from the stent coating into theblood vessel. According to the HPLC analysis, 21.8 μg of the40-O-(2-hydroxy)ethyl-rapamycin was released from the coating in 3 days,or 16.4% of the total drug content of the coating.

Example 45

The release rate of 40-O-(2-hydroxy)ethyl-rapamycin from the stents withcoatings produced by the process under Example 39 were tested using a 3day in vivo process as described in Example 43. In particular, stentsfrom Example 39 were implanted into experimental animals and then thestents were tested by HPLC to determine how much40-O-(2-hydroxy)ethyl-rapamycin diffused from the stent coating into theblood vessel. According to the HPLC analysis, 7.8 μg of the40-O-(2-hydroxy)ethyl-rapamycin was released from the coating in 3 days,or 3.8% of the total drug content of the coating.

Example 46

The release rate of 40-O-(2-hydroxy)ethyl-rapamycin from the stents withcoatings produced by the process under Example 40 were tested using a 3day in vivo process as described in Example 43. In particular, stentsfrom Example 40 were implanted into experimental animals and then thestents were tested by HPLC to determine how much40-O-(2-hydroxy)ethyl-rapamycin diffused from the stent coating into theblood vessel. According to the HPLC analysis, 50.8 μg of the40-O-(2-hydroxy)ethyl-rapamycin was released from the coating in 3 days,or 18% of the total drug content of the coating.

Example 47

The release rate of 40-O-(2-hydroxy)ethyl-rapamycin from the stents withcoatings produced by the process under Example 39 were tested using a 9day in vivo process as described in Example 43. In particular, stentsfrom Example 39 were implanted into experimental animals and then thestents were tested by HPLC to determine how much40-O-(2-hydroxy)ethyl-rapamycin diffused from the stent coating into theblood vessel. According to the HPLC analysis, 29.7% of the40-O-(2-hydroxy)ethyl-rapamycin was released from the coating in 9 days.

Example 48

The release rate of 40-O-(2-hydroxy)ethyl-rapamycin from the stents withcoatings produced by the process under Example 40 were tested using a 9day in vivo process as described in Example 43. In particular, stentsfrom Example 40 were implanted into experimental animals and then thestents were tested by HPLC to determine how much40-O-(2-hydroxy)ethyl-rapamycin diffused from the stent coating into theblood vessel. According to the HPLC analysis, 39.4% of the40-O-(2-hydroxy)ethyl-rapamycin was released from the coating in 9 days.

Example 49

A 13 mm PIXEL stent (available from Guidant Corporation) was coated. Thestent had a yellowish-gold coating that included EVOH and actinomycin D.The ends of the stent were heated with a cauterizer tip for fifteen (15)seconds at a current setting of 2.2 Amps, which corresponded to atemperature of about 106° C. at a distance of about 0.006 inches fromthe stent.

After the stent was exposed to heat from the cauterizer tip, the stentwas submerged in a 50% (w/w) methanol:water bath. After twenty-four (24)hours, the stent was observed to have drug present at the stent endrings as indicated by a yellowish hue. The middle section of the stent,however, was clear, indicating that the drug had been released throughthe polymer. This process was repeated on 40 stents yielding similarresults for all the stents.

Example 50

13 mm PIXEL stents were coated. The stents had yellowish-gold coatingsthat included EVOH and actinomycin D. The stents were separated intothree experimental groups, and the ends of the stents were heated with acauterizer tip according to the parameters shown in Table 10 for eachgroup. After the stents were exposed to heat from the cauterizer tip,the stent was submerged in a 50% (w/w) methanol:water bath. Aftertwenty-four (24) hours, the stents were observed as summarized in Table10.

TABLE 10 Exposure Experimental Current Time Group (Amps) (Seconds)Observation 1 2.0 10 Least gold coloration in the end sections comparedto the stents from Experimental Groups 2 and 3, indicating the leastamount of drug remaining in the stent coating. 2 2.2 8 Moderate goldcoloration in the end sections. 3 2.4 5 Most gold coloration in the endsections compared to the stents from Experimental Groups 1 and 2indicating the most amount of drug remaining in the stent coating.

It was observed that the coating in the middle section of the stents,which did not have significant exposure to heat from the cauterizer tip,was clear. This indicates that the drug had been eluted from the stents.On the other hand, the end rings of the stents which had been exposed toheat from the cauterizer tip still appeared gold in color, indicatingthe presence of drug in the stent coating. The results above indicatethat varying the amount of time and heat exposure can modify the elutionrate of drug from the stent.

Example 51

8 mm PIXEL stents were coated by spraying a 2% (w/w) solution of EVOHand 98% (w/w) dimethylacetamide. The solvent was removed by baking at140° C. for 2 hours. A solution of EVOH and40-O-(2-hydroxy)ethyl-rapamycin in a mixture of 70% (w/w)dimethylacetamide and 30% (w/w) ethanol was spray coated onto thestents. The stents were then baked at 50° C. for 2 hours. A barrierlayer was formed by spraying the stents with a solution of EVOH in amixture of 80% (w/w) dimethylacetamide and 20% (w/w) pentane. Another 2hour bake at 50° C. was performed to remove the solvent.

A select number of stents were analyzed to compare the target coatingformulation with the final coating formulation. The results are asfollows: For the primer layer, there was a target dry weight of 26 μg ofpolymer, and a measured average dry weight of 28±3 μg of polymer. Forthe reservoir layer, the target drug:polymer ratio was 1:1.25, and themeasured average drug content was 128 μg. For the barrier layer, themeasured average dry weight was 84 μg.

Example 52

8 mm PIXEL stents were coated by spraying a 2% (w/w) solution of EVOHand 98% (w/w) dimethylacetamide. The solvent was removed by baking at140° C. for 2 hours. A solution of EVOH and40-O-(2-hydroxy)ethyl-rapamycin in a mixture of 70% (w/w)dimethylacetamide and 30% (w/w) ethanol was spray coated onto thestents. The stents were then baked at 50° C. for 2 hours. A barrierlayer was formed by spraying the stents with a solution of EVOH in amixture of 80% (w/w) dimethylacetamide and 20% (w/w) pentane. Another 2hour bake at 50° C. was performed to remove the solvent.

A select number of stents were analyzed to compare the target coatingformulation with the final coating formulation. The results are asfollows: For the primer layer, there was a target dry weight of 26 μg ofpolymer, and a measured average dry weight of 28±2 μg of polymer. Forthe reservoir layer, the target drug:polymer ratio was 1:1.5, and themeasured average drug content was 130 μg. For the barrier layer, themeasured average dry weight was 81 μg.

After the solvent had been substantially removed and the coatings hadbeen formed, a select number of stents were then heat treated byexposing the stents to a heat of 80° C. for 2 hours.

Example 53

The release rate of 40-O-(2-hydroxy)ethyl-rapamycin from the stents withcoatings produced by the processes under Examples 51 and 52 were testedusing the process described in Example 41. The following Table 11summarizes the results of the release rate procedure for three stentsfrom Example 51:

TABLE 11 Time (hrs) 3 6 9 12 24 32 48 Cumulative Release 15.44 24.6332.20 38.43 56.04 64.81 77.36 from Stent 1 (μg) Cumulative Release 12.7021.29 28.57 34.55 51.19 59.27 71.15 from Stent 2 (μg) Cumulative Release13.00 21.92 29.31 35.40 52.55 60.48 72.05 from Stent 3 (μg)

The following Table 12 summarizes the results of the release rateprocedure for three stents from Example 52:

TABLE 12 Time (hrs) 3 6 9 12 24 32 48 Cumulative Release 5.52 9.37 12.7315.71 24.33 29.20 38.02 from Stent 1 (μg) Cumulative Release 6.73 10.8614.39 17.41 25.99 30.29 38.00 from Stent 2 (μg) Cumulative Release 5.769.14 12.02 14.50 21.21 24.61 31.23 from Stent 3 (μg)

A comparison of the release rates for the stents from Examples 51-52 isgraphically shown in FIG. 12. The results unexpectedly show that thestent coatings that were exposed to thermal treatment in Example 52 havea significantly lower release rate than the stent coatings of Example51.

Example 54

This Example 54 is referred to as the “Porcine Serum Release RateProcedure.” A drug-coated stent was placed on a stent holder of a VankelBio-Dis release rate tester. The stent was dipped into porcine serum,with 0.1% sodium azide added, for 24 hrs. The stent was removed from theporcine serum and the drug solution analyzed by an HPLC procedure todetermine how much drug was released into the porcine serum. The HPLCsystem consisted of a Waters 2690 system with an analytical pump, acolumn compartment (set at 40° C.), an auto-sampler, and a 996 PDAdetector. The column was an YMC Pro C18 (150 mm×4.6 I.D., 3 μm particlesize), maintained at a temperature of 40° C. The mobile phase consistedof 75% acetonitrile and 25% 20 mMolar ammonium acetate. The flow ratewas set on 1 ml/min. The HPLC release rate results were quantified bycomparing the results with a reference standard.

Example 55

Thirteen (13) mm PENTA stents were coated by spraying a 2% (w/w)solution of EVOH and 98% (w/w) dimethylacetamide. The solvent wasremoved by baking at 140° C. for 2 hours. A solution of EVOH and40-O-(2-hydroxy)ethyl-rapamycin in a mixture of 70% (w/w)dimethylacetamide and 30% (w/w) ethanol was spray coated onto thestents. The stents were then baked at 50° C. for 2 hours. A barrierlayer was formed by spraying the stents with a solution of EVOH in amixture of 80% (w/w) dimethylacetamide and 20% (w/w) pentane. Another 2hour bake at 50° C. was performed to remove the solvent.

A select number of stents were analyzed to quantify the coatingcomponents. For the primer layer, there was a target dry weight of 40 μgof polymer, and a measured average dry weight of 45±1 μg of polymer. Forthe reservoir layer, the drug:polymer ratio was 1:1, and the measuredaverage drug content was 151 μg as determined by Example 38. For thebarrier layer, the measured average dry weight was 234 μg.

After the coatings were formed on the stents, a select number of stentswere tested for the drug release rate from the coatings according to theprocedure described in Example 54. It was determined that the averagedrug released in 24 hours was 32.6 μg, or 21.6% of the total.

Example 56

Thirteen (13) mm PENTA stents were coated by spraying a 2% (w/w)solution of EVOH and 98% (w/w) dimethylacetamide. The solvent wasremoved by baking at 140° C. for 2 hours. A solution of EVOH and40-O-(2-hydroxy)ethyl-rapamycin in a mixture of 70% (w/w)dimethylacetamide and 30% (w/w) ethanol was spray coated onto thestents. The stents were then baked at 50° C. for 2 hours. A barrierlayer was formed by spraying the stents with a solution of EVOH in amixture of 80% (w/w) dimethylacetamide and 20% (w/w) pentane. Another 2hour bake at 50° C. was performed to remove the solvent.

A select number of stents were analyzed to quantify the coatingcomponents. For the primer layer, there was a target dry weight of 40 μgof polymer, and a measured average dry weight of 44±3 μg of polymer. Forthe reservoir layer, the drug:polymer ratio was 1:1.8, and the measuredaverage drug content was 97 μg as determined by Example 38. For thebarrier layer, the measured average dry weight was 184 μg.

After the coatings were formed on the stents, a select number of stentswere tested for the drug release rate from the coatings according to theprocedure described in Example 54. It was determined that the averagedrug released in 24 hours was 24.1 μg, or 24.8% of the total.

Example 57

Thirteen (13) mm PENTA stents were coated by spraying a 2% (w/w)solution of EVOH and 98% (w/w) dimethylacetamide. The solvent wasremoved by baking at 140° C. for 2 hours. A solution of EVOH and40-O-(2-hydroxy)ethyl-rapamycin in a mixture of 70% (w/w)dimethylacetamide and 30% (w/w) ethanol was spray coated onto thestents. The stents were then baked at 50° C. for 2 hours. A barrierlayer was formed by spraying the stents with a solution of EVOH in amixture of 80% (w/w) dimethylacetamide and 20% (w/w) pentane. Another 2hour bake at 50° C. was performed to remove the solvent.

A select number of stents were analyzed to quantify the coatingcomponents. For the primer layer, there was a target dry weight of 40 μgof polymer, and a measured average dry weight of 41±1 μg of polymer. Forthe reservoir layer, the drug:polymer ratio was 1:1.8, and the measuredaverage drug content was 227 μg as determined by Example 38. For thebarrier layer, the measured average dry weight was 181 μg.

After the coatings were formed on the stents, a select number of stentswere tested for the drug release rate from the coatings according to theprocedure described in Example 54. It was determined that the averagedrug released in 24 hours was 27.5 μg, or 12.1% of the total.

Example 58

Thirteen (13) mm PENTA stents were coated by spraying a 2% (w/w)solution of EVOH and 98% (w/w) dimethylacetamide. The solvent wasremoved by baking at 140° C. for 2 hours. A solution of EVOH and40-O-(2-hydroxy)ethyl-rapamycin in a mixture of 70% (w/w)dimethylacetamide and 30% (w/w) ethanol was spray coated onto thestents. The stents were then baked at 50° C. for 2 hours. No barrierlayer was applied for this Example.

A select number of stents were analyzed to quantify the coatingcomponents. For the primer layer, there was a target dry weight of 40 μgof polymer, and a measured average dry weight of 44±2 μg of polymer. Forthe reservoir layer, the drug:polymer ratio was 1:1.8, and the measuredaverage drug content was 221 μg as determined by Example 38.

After the coatings were formed on the stents, a select number of stentswere tested for the drug release rate from the coatings according to theprocedure described in Example 54. It was determined that the averagedrug released in 24 hours was 129.4 μg, or 58.55% of the total.

Example 59

PENTA stents, 13 mm, were coated by spraying a 2% (w/w) solution of EVOHand 98% (w/w) dimethylacetamide. The solvent was removed by baking at140° C. for 2 hours. A solution of EVOH and40-O-(2-hydroxy)ethyl-rapamycin in a mixture of 70% (w/w)dimethylacetamide and 30% (w/w) ethanol was spray coated onto thestents. The stents were then baked at 50° C. for 2 hours. A barrierlayer was formed by spraying the stents with a solution of EVOH in amixture of 80% (w/w) dimethylacetamide and 20% (w/w) pentane. Another 2hour bake at 50° C. was performed to remove the solvent.

A select number of stents were analyzed to quantify the coatingcomponents. For the primer layer, there was a target dry weight of 40 μgof polymer, and a measured average dry weight of 42 μg of polymer. Forthe reservoir layer, the drug:polymer ratio was 1:1.5, and the measuredaverage drug content was 184 μg as determined by Example 38. For thebarrier layer, the measured average dry weight was 81 μg.

After the coatings were formed on the stents, a select number of stentswere tested for the drug release rate from the coatings according to theprocedure described in Example 54. It was determined that the averagedrug released in 24 hours was 70.1 μg, or 38.1% of the total.

Example 60

PIXEL stents, 8 mm, were coated by spraying a 2% (w/w) solution of EVOHand 98% (w/w) dimethylacetamide. The solvent was removed by baking at140° C. for 2 hours. A solution of EVOH and40-O-(2-hydroxy)ethyl-rapamycin in a mixture of 70% (w/w)dimethylacetamide and 30% (w/w) ethanol was spray coated onto thestents. The stents were then baked at 50° C. for 2 hours. A barrierlayer was formed by spraying the stents with a solution of EVOH in amixture of 80% (w/w) dimethylacetamide and 20% (w/w) pentane. Another 2hour bake at 50° C. was performed to remove the solvent.

A select number of stents were analyzed to quantify the coatingcomponents. For the primer layer, there was a target dry weight of 40 μgof polymer, and a measured average dry weight of 45±1 μg of polymer. Forthe reservoir layer, the drug:polymer ratio was 1:1.75, and the measuredaverage drug content was 200 μg as determined by Example 38. For thebarrier layer, the measured average dry weight was 180 μg.

After the coatings were formed on the stents, a select number of stentswere tested for the drug release rate from the coatings according to theprocedure described in Example 54. It was determined that the averagedrug released in 24 hours was 39.0 μg, or 19.5% of the total.

Example 61

PIXEL stents, 8 mm, were coated by spraying a 2% (w/w) solution of EVOHand 98% (w/w) dimethylacetamide. The solvent was removed by baking at140° C. for 2 hours. A solution of EVOH and40-O-(2-hydroxy)ethyl-rapamycin in a mixture of 70% (w/w)dimethylacetamide and 30% (w/w) ethanol was spray coated onto thestents. The stents were then baked at 50° C. for 2 hours. A barrierlayer was formed by spraying the stents with a solution of EVOH in amixture of 80% (w/w) dimethylacetamide and 20% (w/w) pentane. Another 2hour bake at 50° C. was performed to remove the solvent.

A select number of stents were analyzed to quantify the coatingcomponents. For the primer layer, there was a target dry weight of 40 μgof polymer, and a measured average dry weight of 41±4 μg of polymer. Forthe reservoir layer, the drug:polymer ratio was 1:1, and the measuredaverage drug content was 167 μg as determined by Example 38. For thebarrier layer, the measured average dry weight was 184 μg.

After the coatings were formed on the stents, a select number of stentswere tested for the drug release rate from the coatings according to theprocedure described in Example 54. It was determined that the averagedrug released in 24 hours was 6.0 μg, or 3.6% of the total.

Example 62

PIXEL stents, 8 mm, were coated by spraying a 2% (w/w) solution of EVOHand 98% (w/w) dimethylacetamide. The solvent was removed by baking at140° C. for 2 hours. A solution of EVOH and40-O-(2-hydroxy)ethyl-rapamycin in a mixture of 70% (w/w)dimethylacetamide and 30% (w/w) ethanol was spray coated onto thestents. The stents were then baked at 50° C. for 2 hours. A barrierlayer was formed by spraying the stents with a solution of EVOH in amixture of 80% (w/w) dimethylacetamide and 20% (w/w) pentane. Another 2hour bake at 50° C. was performed to remove the solvent.

A select number of stents were analyzed to quantify the coatingcomponents. For the primer layer, there was a target dry weight of 26 μgof polymer, and a measured average dry weight of 24±2 μg of polymer. Forthe reservoir layer, the drug:polymer ratio was 1:1.25, and the measuredaverage drug content was 120 μg as determined by Example 38. For thebarrier layer, the measured average dry weight was 138 μg.

After the coatings were formed on the stents, a select number of stentswere tested for the drug release rate from the coatings according to theprocedure described in Example 54. It was determined that the averagedrug released in 24 hours was 11.0 μg, or 9.2% of the total.

Example 63

Thirteen (13) mm PENTA stents were coated by spraying a 2% (w/w)solution of EVOH and 98% (w/w) dimethylacetamide. The solvent wasremoved by baking at 140° C. for 2 hours. A solution of EVOH and40-O-(2-hydroxy)ethyl-rapamycin in a mixture of 70% (w/w)dimethylacetamide and 30% (w/w) ethanol was spray coated onto thestents. The stents were then baked at 50° C. for 2 hours. A barrierlayer was formed by spraying the stents with a solution of 1% (w/w)polybutylmethacrylate (“PBMA”), 5.7% (w/w) acetone, 50% (w/w) xylene and43.3% (w/w) HFE FLUX REMOVER (Techspray, Amarillo, Tex.). Another 2 hourbake at 50° C. was performed to remove the solvent.

A select number of stents were analyzed to quantify the coatingcomponents. For the primer layer, there was a target dry weight of 40 μgof polymer, and a measured average dry weight of 44±4 μg of polymer. Forthe reservoir layer, the drug:polymer ratio was 1:1, and the measuredaverage drug content was 183 μg as determined by Example 38. For thebarrier layer, the measured average dry weight was 168 μg.

After the coatings were formed on the stents, a select number of stentswere tested for the drug release rate from the coatings according to theprocedure described in Example 54. It was determined that the averagedrug released in 24 hours was 21.6 μg, or 11.8% of the total.

Example 64

Thirteen (13) mm PENTA stents were coated by spraying a 2% (w/w)solution of EVOH and 98% (w/w) dimethylacetamide. The solvent wasremoved by baking at 140° C. for 2 hours. A solution of EVOH and40-O-(2-hydroxy)ethyl-rapamycin in a mixture of 70% (w/w)dimethylacetamide and 30% (w/w) ethanol was spray coated onto thestents. The stents were then baked at 50° C. for 2 hours. A barrierlayer was formed by spraying the stents with a solution of 1% (w/w)PBMA, 5.7% (w/w) acetone, 50% (w/w) xylene and 43.3% (w/w) HFE FLUXREMOVER. Another 2 hour bake at 50° C. was performed to remove thesolvent.

A select number of stents were analyzed to quantify the coatingcomponents. For the primer layer, there was a target dry weight of 40 μgof polymer, and a measured average dry weight of 41±2 μg of polymer. Forthe reservoir layer, the drug:polymer ratio was 1:1.8, and the measuredaverage drug content was 102 μg as determined by Example 38. For thebarrier layer, the measured average dry weight was 97 μg.

After the coatings were formed on the stents, a select number of stentswere tested for the drug release rate from the coatings according to theprocedure described in Example 54. It was determined that the averagedrug released in 24 hours was 9.1 μg, or 8.9% of the total.

Example 65

Eight (8) mm PIXEL stents were coated by spraying a 2% (w/w) solution ofEVOH and 98% (w/w) dimethylacetamide. The solvent was removed by bakingat 140° C. for 2 hours. A solution of EVOH and40-O-(2-hydroxy)ethyl-rapamycin in a mixture of 70% (w/w)dimethylacetamide and 30% (w/w) ethanol was spray coated onto thestents. The stents were then baked at 50° C. for 2 hours. A barrierlayer was formed by spraying the stents with a solution of 1% (w/w)PBMA, 5.7% (w/w) acetone, 50% (w/w) xylene and 43.3% (w/w) HFE FLUXREMOVER (Techspray, Amarillo, Tex.). Another 2 hour bake at 50° C. wasperformed to remove the solvent.

A select number of stents were analyzed to quantify the coatingcomponents. For the primer layer, there was a target dry weight of 26 μgof polymer, and a measured average dry weight of 27±2 μg of polymer. Forthe reservoir layer, the drug:polymer ratio was 1:1.25, and the measuredaverage drug content was 120 μg as determined by Example 38. For thebarrier layer, the measured average dry weight was 68 μg.

After the coatings were formed on the stents, a select number of stentswere tested for the drug release rate from the coatings according to theprocedure described in Example 54. It was determined that the averagedrug released in 24 hours was 22.0 μg, or 18.3% of the total.

Example 66

A select number of stents from Example 39 were tested for the drugrelease rate from the coatings according to the procedure described inExample 54. It was determined that the average drug released in 24 hourswas 22.8 μg, or 11.1% of the total.

Example 67

A select number of stents from Example 40 were tested for the drugrelease rate from the coatings according to the procedure described inExample 54. It was determined that the average drug released in 24 hourswas 57.0 μg, or 20.2% of the total.

Example 68

Two stents were coated by spraying a 2% (w/w) solution of EVOH and 98%(w/w) dimethylacetamide to form a primer layer. For the primer layer,there was a target dry weight of 100 μg of polymer, and the measured dryweights were 93 μg and 119 μg, respectively. The two stents were thencoated with an EVOH-40-O-(2-hydroxy)ethyl-rapamycin blend at adrug:polymer ratio of 2:1 to produce a reservoir layer. Afterapplication, it was determined that the reservoir layers had weights of610 μg and 590 μg, respectively. From the total weight of the reservoirlayers and the drug:polymer ratio, it was estimated that the coatingscontained about 407 μg and 393 μg of 40-O-(2-hydroxy)ethyl-rapamycin,respectively. Polymeric barrier layers were also applied to the stentsand it was determined that the weights of the barrier layers were 279 μgand 377 μg, respectfully.

The stents from this Example were then sterilized using an ethyleneoxide sterilization process. In particular, the stents were placed in achamber and exposed to ethylene oxide gas for 6 hours at 130-140° F.,with a relative humidity of 45-80%. The stents were then aerated forabout 72 hours at 110-130° F.

After sterilization, the coatings were then analyzed using an HPLC todetermine the peak purity of the drug in the stent coatings. It wasdetermined that the 40-O-(2-hydroxy)ethyl-rapamycin in the coatings hadpeak purities of about greater than 95%. FIG. 13 is a chromatographshowing the peak purity the 40-O-(2-hydroxy)ethyl-rapamycin in one ofthe coatings, labeled “ETO,” as compared to a reference standard for40-O-(2-hydroxy)ethyl-rapamycin, labeled “Ref. Std.”

Example 69

Two stents were coated by spraying a 2% (w/w) solution of EVOH and 98%(w/w) dimethylacetamide to form a primer layer. For the primer layer,there was a target dry weight of 100 μg of polymer, and the measured dryweights were 99 μg and 94 μg, respectively. The two stents were thencoated with an EVOH-40-O-(2-hydroxy)ethyl-rapamycin blend at adrug:polymer ratio of 2:1 to produce a reservoir layer. Afterapplication, it was determined that the reservoir layers had weights of586 μg and 588 μg, respectively. From the total weight of the reservoirlayers and the drug:polymer ratio, it was estimated that the coatingscontained about 391 μg and 392 μg of 40-O-(2-hydroxy)ethyl-rapamycin,respectively. Polymeric barrier layers were also applied to the stentsand it was determined that the weights of the barrier layers were 380 μgand 369 μg, respectfully.

The stents from this Example were then sterilized using an e-beamsterilization process. In particular, the stents were placed in a stentcontainer which was run through an e-beam chamber. While moving throughthe e-beam chamber via a conveyor belt, the stent container was exposedto an e-beam with a constant energy level so that the stent containerreceived between 33.11 and 46.24 Kgy. The stent therefore at any pointalong the length of the stent received at a minimum 25 Kgy.

After sterilization, the coating was then analyzed using an HPLC todetermine the peak purity of the drug in the stent coating. It wasdetermined that the 40-O-(2-hydroxy)ethyl-rapamycin in the coating had apeak purity of about greater than 95%. FIG. 13 is a chromatographshowing the peak purity the 40-O-(2-hydroxy)ethyl-rapamycin in one ofthe coatings, labeled “e-beam,” as compared to a reference standard for40-O-(2-hydroxy)ethyl-rapamycin, labeled “Ref. Std.”

Example 70

Thirteen (13) mm PENTA stents were coated by spraying a 2% (w/w)solution of EVOH and 98% (w/w) dimethylacetamide. The solvent wasremoved by baking at 140° C. for 2 hours. A solution of EVOH and40-O-(2-hydroxy)ethyl-rapamycin in a mixture of 70% (w/w)dimethylacetamide and 30% (w/w) ethanol was spray coated onto thestents. The stents were then baked at 50° C. for 2 hours. A barrierlayer was formed by spraying the stents with a solution of EVOH in amixture of 80% (w/w) dimethylacetamide and 20% (w/w) pentane. Another 2hour bake at 50° C. was performed to remove the solvent.

A select number of stents were analyzed to quantify the coatingcomponents. For the primer layer, there was a target dry weight of 40 μgof polymer, and a measured average dry weight of 44±3 μg of polymer. Forthe reservoir layer, the drug:polymer ratio was 1:2, and the measuredaverage drug content was 245 μg as determined by Example 38. For thebarrier layer, the measured average dry weight was 104 μg.

After the coatings were formed on the stents, a select number of stentswere tested for the drug release rate from the coatings according to theprocedure described in Example 54. It was determined that the averagedrug released in 24 hours was 23.5 μg, or 9.6% of the total.

Example 71

Thirteen (13) mm PENTA stents were coated by spraying a 2% (w/w)solution of EVOH and 98% (w/w) dimethylacetamide. The solvent wasremoved by baking at 140° C. for 2 hours. A solution of EVOH and40-O-(2-hydroxy)ethyl-rapamycin in a mixture of 70% (w/w)dimethylacetamide and 30% (w/w) ethanol was spray coated onto thestents. The stents were then baked at 50° C. for 2 hours. A barrierlayer was formed by spraying the stents with a solution of EVOH in amixture of 80% (w/w) dimethylacetamide and 20% (w/w) pentane. Another 2hour bake at 50° C. was performed to remove the solvent.

A select number of stents were analyzed to quantify the coatingcomponents. For the primer layer, there was a target dry weight of 40 μgof polymer, and a measured average dry weight of 45±3 μg of polymer. Forthe reservoir layer, the drug:polymer ratio was 1:1.5, and the measuredaverage drug content was 337 μg as determined by Example 38. For thebarrier layer, the measured average dry weight was 169 μg.

After the coatings were formed on the stents, a select number of stentswere tested for the drug release rate from the coatings according to theprocedure described in Example 54. It was determined that the averagedrug released in 24 hours was 37.1 μg, or 11.0% of the total.

Example 72

Stents from Example 70 and stents from Example 71 were sterilizedaccording to the process described in Example 68. The released rates ofthe drug in the stent coatings of sterilized stents and non-sterilizedwere then tested according to the process described in Example 41. Theresults of the release rate test are graphically shown in FIG. 14.

Example 73

A 13 mm PENTA stent can be coated by spraying a solution of EVOH,40-O-(2-hydroxy)ethyl-rapamycin and ethanol onto the stent. The stent isthen baked at 50° C. for 2 hours to yield a reservoir coating with 300μg of EVOH and 300 μg of 40-O-(2-hydroxy)ethyl-rapamycin. A barrierlayer can be formed by spraying the stent with a solution of EVOH andpentane. A second 2 hour bake at 50° C. can be performed to remove thesolvent to yield a barrier coating with 320 μg of EVOH.

Example 74

A 13 mm PENTA stent can be coated by spraying a solution of EVOH andDMAC onto the stent. The solvent is removed by baking at 140° C. for 2hours to yield a primer coating with 100 μg of EVOH. A reservoir layercan be applied by spraying a solution of EVOH,40-O-(2-hydroxy)ethyl-rapamycin and ethanol onto the stent. The stent isthen baked at 50° C. for 2 hours to yield a reservoir coating with 200μg of EVOH and 400 μg of 40-O-(2-hydroxy)ethyl-rapamycin. A barrierlayer can be formed by spraying the stent with a solution of EVOH andpentane. A second 2 hour bake at 50° C. is performed to remove thesolvent to yield a barrier coating with 350 μg of EVOH.

Example 75

A 13 mm PENTA stent can be coated by spraying a solution of EVOH,40-O-(2-hydroxy)ethyl-rapamycin and ethanol onto the stent. The stent isthen baked at 50° C. for 2 hours to yield a reservoir coating with 500μg of EVOH and 250 μg of 40-O-(2-hydroxy)ethyl-rapamycin. A barrierlayer can be formed by spraying the stent with a solution of EVOH andpentane. A second 2 hour bake at 50° C. is performed to remove thesolvent to yield a barrier coating with 300 μg of EVOH.

Example 76

A 13 mm PENTA stent can be coated by spraying a solution of EVOH,40-O-(2-hydroxy)ethyl-rapamycin and ethanol onto the stent. The stent isthen baked at 50° C. for 2 hours to yield a reservoir coating with 475μg of EVOH and 175 μg of 40-O-(2-hydroxy)ethyl-rapamycin. A barrierlayer can be formed by spraying the stent with a solution of EVOH andpentane. A second 2 hour bake at 50° C. is performed to remove thesolvent to yield a barrier coating with 300 μg of EVOH.

Example 77

An 8 mm PIXEL stent can be coated by spraying a solution of EVOH and40-O-(2-hydroxy)ethyl-rapamycin in a mixture of dimethylacetamide andethanol onto the stent. The stent is then baked at 50° C. for 2 hours toyield a reservoir coating with 400 μg of EVOH and 200 μg of40-O-(2-hydroxy)ethyl-rapamycin. A barrier layer can be formed byspraying the stent with a solution of EVOH and a mixture ofdimethylacetamide and pentane. A second 2 hour bake at 50° C. isperformed to remove the solvent to yield a barrier coating with 300 μgof EVOH.

Example 78

An 8 mm PIXEL stent can be coated by spraying a solution of EVOH and40-O-(2-hydroxy)ethyl-rapamycin in a mixture of dimethylacetamide andethanol onto the stent. The stent is then baked at 50° C. for 2 hours toyield a reservoir coating with 400 μg of EVOH and 200 μg of40-O-(2-hydroxy)ethyl-rapamycin. A barrier layer can be formed byspraying the stent with a solution of PBMA and HFE FLUX REMOVER. Asecond 2 hour bake at 50° C. is performed to remove the solvent to yielda barrier coating with 150 μg of PBMA.

Example 79

An 8 mm PIXEL stent can be coated by spraying a solution of EVOH and40-O-(2-hydroxy)ethyl-rapamycin in a mixture of dimethylacetamide andethanol onto the stent. The stent is then baked at 50° C. for 2 hours toyield a reservoir coating with 200 μg of EVOH and 200 μg of40-O-(2-hydroxy)ethyl-rapamycin. A barrier layer can be formed byspraying the stent with a solution of EVOH and a mixture ofdimethylacetamide and pentane. A second 2 hour bake at 50° C. isperformed to remove the solvent to yield a barrier coating with 200 μgof EVOH.

Example 80

An 8 mm PIXEL stent can be coated by spraying a solution of EVOH and40-O-(2-hydroxy)ethyl-rapamycin in a mixture of dimethylacetamide andethanol onto the stent. The stent is then baked at 50° C. for 2 hours toyield a reservoir coating with 200 μg of EVOH and 200 μg of40-O-(2-hydroxy)ethyl-rapamycin. A barrier layer can formed by sprayingthe stent with a solution of PBMA and HFE FLUX REMOVER. A second 2 hourbake at 50° C. is performed to remove the solvent to yield a barriercoating with 150 μg of PBMA.

Example 81

An 8 mm PIXEL stent can be coated by spraying a solution of EVOH and40-O-(2-hydroxy)ethyl-rapamycin in a mixture of dimethylacetamide andethanol onto the stent. The stent is then baked at 50° C. for 2 hours toyield a reservoir coating with 200 μg of EVOH and 200 μg of40-O-(2-hydroxy)ethyl-rapamycin. A barrier layer can be formed byspraying the stent with a solution of EVOH and a mixture ofdimethylacetamide and pentane. A second 2 hour bake at 50° C. isperformed to remove the solvent to yield a barrier coating with 200 μgof EVOH.

Example 82

An 8 mm PIXEL stent can be coated by spraying a solution of EVOH and40-O-(2-hydroxy)ethyl-rapamycin in a mixture of dimethylacetamide andethanol onto the stent. The stent is then baked at 50° C. for 2 hours toyield a reservoir coating with 200 μg of EVOH and 200 μg of40-O-(2-hydroxy)ethyl-rapamycin. A barrier layer can be formed byspraying the stent with a solution of PBMA and HFE FLUX REMOVER. Asecond 2 hour bake at 50° C. is performed to remove the solvent to yielda barrier coating with 100 μg of PBMA.

Example 83

An 8 mm PIXEL stent can be coated by spraying a solution of EVOH and40-O-(2-hydroxy)ethyl-rapamycin in a mixture of dimethylacetamide andethanol onto the stent. The stent is then baked at 50° C. for 2 hours toyield a reservoir coating with 270 μg of EVOH and 150 μg of40-O-(2-hydroxy)ethyl-rapamycin. A barrier layer can be formed byspraying the stent with a solution of EVOH and a mixture ofdimethylacetamide and pentane. A second 2 hour bake at 50° C. isperformed to remove the solvent to yield a barrier coating with 150 μgof EVOH.

Example 84

An 8 mm PIXEL stent can be coated by spraying a solution of EVOH and40-O-(2-hydroxy)ethyl-rapamycin in a mixture of dimethylacetamide andethanol onto the stent. The stent is then baked at 50° C. for 2 hours toyield a reservoir coating with 170 μg of EVOH and 150 μg of40-O-(2-hydroxy)ethyl-rapamycin. A barrier layer can be formed byspraying the stent with a solution of PBMA and HFE FLUX REMOVER. Asecond 2 hour bake at 50° C. is performed to remove the solvent to yielda barrier coating with 75 μg of PBMA.

Example 85

An 8 mm PIXEL stent can be coated by spraying a solution of EVOH and40-O-(2-hydroxy)ethyl-rapamycin in a mixture of dimethylacetamide andethanol onto the stent. The stent is then baked at 50° C. for 2 hours toyield a reservoir coating with 150 μg of EVOH and 150 μg of40-O-(2-hydroxy)ethyl-rapamycin. A barrier layer can be formed byspraying the stent with a solution of EVOH and a mixture ofdimethylacetamide and pentane. A second 2 hour bake at 50° C. isperformed to remove the solvent to yield a barrier coating with 200 μgof EVOH. A finishing layer can then applied by spraying the stent with asolution of EVOH, polyethylene oxide (molecular weight of 17.5 K)(“PEO”) and dimethylacetamide. The stent is baked at 50° C. for 2 hoursto remove the solvent to yield a finishing coating with 83 μg of EVOHand 17 μg of PEO.

Example 86

An 8 mm PIXEL stent can be coated by spraying a solution of EVOH and40-O-(2-hydroxy)ethyl-rapamycin in a mixture of dimethylacetamide andethanol onto the stent. The stent is then baked at 50° C. for 2 hours toyield a reservoir coating with 270 μg of EVOH and 150 μg of40-O-(2-hydroxy)ethyl-rapamycin. A barrier layer can formed by sprayingthe stent with a solution of EVOH and a mixture of dimethylacetamide andpentane. A second 2 hour bake at 50° C. is performed to remove thesolvent to yield a barrier coating with 150 μg of EVOH. A finishinglayer can then applied by spraying the stent with a solution of EVOH,PEO and dimethylacetamide. The stent is baked at 50° C. for 2 hours toremove the solvent to yield a finishing coating with 83 μg of EVOH and17 μg of PEO.

Example 87

An 8 mm PIXEL stent can be coated by spraying a solution of EVOH and40-O-(2-hydroxy)ethyl-rapamycin in a mixture of dimethylacetamide andethanol onto the stent. The stent is then baked at 50° C. for 2 hours toyield a reservoir coating with 200 μg of EVOH and 200 μg of40-O-(2-hydroxy)ethyl-rapamycin. A barrier layer can be formed byspraying the stent with a solution of EVOH and a mixture ofdimethylacetamide and pentane. A second 2 hour bake at 50° C. isperformed to remove the solvent to yield a barrier coating with 100 μgof EVOH.

Example 88

An 8 mm PIXEL stent can be coated by spraying a solution of EVOH and40-O-(2-hydroxy)ethyl-rapamycin in a mixture of dimethylacetamide andethanol onto the stent. The stent is then baked at 50° C. for 2 hours toyield a reservoir coating with 200 μg of EVOH and 200 μg of40-O-(2-hydroxy)ethyl-rapamycin. A barrier layer can be formed byspraying the stent with a solution of EVOH, KYNAR and HFE FLUX REMOVER.A second 2 hour bake at 50° C. is performed to remove the solvent toyield a barrier coating with 50 μg of EVOH and 50 μg of KYNAR.

Example 89

An 8 mm PIXEL stent can be coated by spraying a solution of EVOH and40-O-(2-hydroxy)ethyl-rapamycin in a mixture of dimethylacetamide andethanol onto the stent. The stent is then baked at 50° C. for 2 hours toyield a reservoir coating with 350 μg of EVOH and 200 μg of40-O-(2-hydroxy)ethyl-rapamycin. A barrier layer is formed by sprayingthe stent with a solution of EVOH and a mixture of dimethylacetamide andpentane. A second 2 hour bake at 50° C. is performed to remove thesolvent to yield a barrier coating with 200 μg of EVOH.

Example 90

An 8 mm PIXEL stent can be coated by spraying a solution of EVOH and40-O-(2-hydroxy)ethyl-rapamycin in a mixture of dimethylacetamide andethanol onto the stent. The stent is then baked at 50° C. for 2 hours toyield a reservoir coating with 350 μg of EVOH and 200 μg of40-O-(2-hydroxy)ethyl-rapamycin. A barrier layer can be formed byspraying the stent with a solution of PBMA and HFE FLUX REMOVER. Asecond 2 hour bake at 50° C. is performed to remove the solvent to yielda barrier coating with 100 μg of PBMA.

Example 91

An 8 mm PIXEL stent can be coated by spraying a solution of EVOH and40-O-(2-hydroxy)ethyl-rapamycin in a mixture of dimethylacetamide andethanol onto the stent. The stent is then baked at 50° C. for 2 hours toyield a reservoir coating with 350 μg of EVOH and 200 μg of40-O-(2-hydroxy)ethyl-rapamycin. A barrier layer can be formed byspraying the stent with a solution of EVOH and a mixture ofdimethylacetamide and pentane. A second 2 hour bake at 50° C. isperformed to remove the solvent to yield a barrier coating with 200 μgof EVOH.

Example 92

An 8 mm PIXEL stent is coated by spraying a solution of EVOH and40-O-(2-hydroxy)ethyl-rapamycin in a mixture of dimethylacetamide andethanol onto the stent. The stent is then baked at 50° C. for 2 hours toyield a reservoir coating with 350 μg of EVOH and 200 μg of40-O-(2-hydroxy)ethyl-rapamycin. A barrier layer can be formed byspraying the stent with a solution of EVOH and a mixture ofdimethylacetamide and pentane. A second 2 hour bake at 50° C. isperformed to remove the solvent to yield a barrier coating with 100 μgof EVOH. A finishing layer can then be applied by spraying the stentwith a solution of EVOH, PEO and dimethylacetamide. The stent is bakedat 50° C. for 2 hours to remove the solvent to yield a finishing coatingwith 83 μg of EVOH and 17 μg of PEO.

Example 93

An 8 mm PIXEL stent can be coated by spraying a solution of EVOH and40-O-(2-hydroxy)ethyl-rapamycin in a mixture of dimethylacetamide andethanol onto the stent. The stent is then baked at 50° C. for 2 hours toyield a reservoir coating with 350 μg of EVOH and 200 μg of40-O-(2-hydroxy)ethyl-rapamycin. A barrier layer can be formed byspraying the stent with a solution of PBMA and HFE FLUX REMOVER. Asecond 2 hour bake at 50° C. is performed to remove the solvent to yielda barrier coating with 75 μg of PBMA. A finishing layer can then beapplied by spraying the stent with a solution of PBMA, PEO anddimethylacetamide. The stent is baked at 50° C. for 2 hours to removethe solvent to yield a finishing coating with 62.5 μg of PBMA and 12.5μg of PEO.

Example 94

The purpose of this study was to evaluate40-O-(2-hydroxy)ethyl-rapamycin in its ability to prevent excessiveneointimal proliferation following stenting in a 28-day porcine coronaryartery stent model. Specifically, two formulations of40-O-(2-hydroxy)ethyl-rapamycin and EVOH were coated onto Multi-LinkPENTA™ stents. These two formulations of drug eluting stents werecompared to a polymer control and a bare stent control in terms ofsafety and efficacy in a 28 day in vivo porcine model.

The following are the materials used for this Example:

-   -   1. Experimental animals: Thirteen 30-45 kg Yorkshire cross pigs,        male or female.    -   2. Stents: MULTI-LINK PENTA™ (3.0×13 mm) with the following        coatings:        -   Six Bare stainless steel stents (Control Group).        -   Nine True Coat™ stents (EVOH Polymer Control Group) have 800            μg of EVOH.        -   Nine stents having a reservoir layer with            40-O-(2-hydroxy)ethyl-rapamycin (205 μg of drug, with a drug            to polymer ratio of 1:1.75) and a 189 μg EVOH topcoat.        -   Nine stents having a reservoir layer with            40-O-(2-hydroxy)ethyl-rapamycin (282 μg of drug, with a drug            to polymer ratio of 1:1.6) and a 130 μg EVOH topcoat.    -   3. BMW™ wires 0.014″, 190 cm.    -   4. Guide wire 0.035″, 190 cm.    -   5. Viking guide catheters, 7F.    -   6. Introducer sheaths (8-10F).    -   7. ACS 20/20 Indeflator™ Inflation Device.    -   8. Heparinized saline.    -   9. Nitroglycerin, Lidocaine, other inotropic/chronotropic drugs.    -   10. Standard surgical equipment, anesthetic, and medications as        necessary.    -   11. Respiratory and hemodynamic monitoring systems.    -   12. Positive pressure ventilator and associated breathing        circuits.    -   13. ACT machine and accessories.    -   14. PTCA accessories.    -   15. Ambulatory defibrillator.    -   16. Fluoroscopy equipment.    -   17. Non-ionic contrast agent.

Thirteen (13) pigs were evaluated in this study. Eleven (11) pigs wereused for the 28-day chronic study in order to evaluate the vascularresponse to the drug eluting stents. Three stents were implanted in eachanimal. Stents were deployed in the right coronary artery (RCA), theleft anterior descending artery (LAD), and the left circumflex coronaryartery (LCX) for the 28-day duration. All stents were deployed at a1.1:1 stent:artery ratio allowing slight to moderate injury in order toassess the drugs ability to prevent excessive neointimal proliferationfollowing stenting. Each stented vessel underwent follow up angiographyand histo-pathological evaluation in order to assess the chronicvascular cellular response and to assess if the drug has any effect inreducing neointimal proliferation compared to controls.

Pre-clinical animal testing was performed in accordance with the NIHGuide for the Care and Use of Laboratory Animals. The animals werehoused at an animal facility. Animals were shipped off-site for chronichousing once fully recovered from the procedure. All animal care,husbandry, and veterinary issues fell under the responsibility of theinstitutional veterinarian.

All animals received aspirin (325 mg PO) and Ticlopidine (500 mg PO)once daily for three days prior to undergoing stent placement. All stentplacement procedures were performed on anesthetized pigs using aseptictechnique. A baseline angiogram was obtained and three target sites (1per coronary vessel) were selected with 2.7-3.2 mm vessel diameter.Vessel size was determined by using the guiding catheter as a referenceor with on line Quantitative Coronary Angiographic analysis (QCA). Afterselection of a target site, the appropriate products was prepared foruse and stents were deployed in such a manner as to achieve a 1.1:1.0overstretch of the vessel. After recovery from anesthesia, each pig wastreated with Ticlopidine (500 mg PO) once daily for the duration of thestudy and Aspirin (325 mg PO) once daily for the duration of the study.

After 28 days each animal underwent a follow-up angiography in order tore-assess patency, deployment and placement of stents. Additionally,online QCA measurements were made to provide angiographic estimates ofthe minimal luminal diameters (MLD) and percentage of vessel lumenrestenosis. All follow-up angiography procedures were performed onanesthetized pigs using clean technique. Aseptic technique was notnecessary as this is an acute procedure.

The pigs were euthanized immediately following the follow-upangiography. The hearts were removed, perfused with saline and pressureperfusion fixed with formalin before being placed into a labeledcontainer with formalin and submitted for pathological evaluation.Sections of the treated coronary arteries were sent to a contractedpathology site. Five cross sections of the stented vessel were preparedincluding one section of each vessel ends and three sections of thestented area. The tissue was stained with haemoatoxylin and eosin andwith an elastin stain. A morphometric analysis of the stented arterieswas performed which included an assessment of stent strut position anddetermination of vessel/lumen areas, percent stenosis, injury scores,intimal and medial areas and intima/media ratios.

The following is a list of the general procedure used for this Example:

A. Animal Preparation

-   -   1. Administer Aspirin (325 mg PO) and Ticlopidine (500 mg PO)        once daily starting 3 days prior to stent implantation.    -   2. Sedate the pigs according to the institutional standard        operating procedure.    -   3. Intubate the trachea via an oral approach.    -   4. Deliver isoflurane (up to 5%) to achieve and maintain an        adequate plane of anesthesia.    -   5. Shave the sheath introduction area free of hair and scrub the        surgical site with surgical soap and/or antiseptic solution.    -   6. Place a 8-10F introducer sheath into the right or left        femoral artery.    -   7. Obtain an arterial blood sample for a baseline ACT.    -   8. Record rectal temperature.    -   9. Administer heparin 200 units/kg IV (not to exceed 100,000        units) and obtain a blood sample for measurement of ACT 5-10        minutes later.    -   10. Repeat heparin as needed to maintain ACT≧300 seconds.    -   11. Measure and record arterial blood pressure, heart rate and        electrocardiogram (ECG).

B. Angiography for vessel selection

-   -   1. Advance the guiding catheter over the guidewire into the        aortic arch and cannulate the desired vessel.    -   2. Administer nitroglycerin 200 μg intra-luminally prior to        baseline angiography.    -   3. Perform baseline angiogram and record images on cine.    -   4. With the diameter of the guiding catheter as a reference,        select vasculature that will allow a target stent to artery        ratio of 1.1:1.0.

C. Stent Preparation and Deployment

-   -   1. Perform online QCA and measure baseline proximal, target, and        distal reference sites.    -   2. Administer nitroglycerin (200 μg) intra-luminally prior to        stent deployment, then as needed to control coronary artery        vasospasm.    -   3. Inspect the stent delivery system. Ensure that the stent is        correctly positioned on the balloon. Inspect the stent for any        abnormalities.    -   4. Flush guidewire lumen with heparinized saline until fluid        exits the guidewire notch.    -   5. Prepare Indeflator/syringe with diluted (approximately 50:50)        contrast medium.    -   6. Attach syringe to test catheter inflation port; use standard        techniques to fill the inflation lumen with diluted contrast.    -   7. Purge syringe and test catheter inflation lumen of all air.    -   8. Purge Indeflator of all air and attach to test catheter        inflation port.    -   9. Position an appropriate guidewire in the distal bed of the        target artery.    -   10. Insert the stent delivery system through the guiding        catheter over the guidewire.    -   11. Advance the stent delivery system to the pre-selected        arterial deployment site.    -   12. Position balloon for inflation.    -   13. Refer to IFU for inflation strategy. If no IFU available,        inflate the balloon at a slow steady rate to a pressure that        expands the stent to the desired diameter. Hold at this pressure        for 30 seconds.    -   14. Record inflated balloon by pulling image on cine. Perform        on-line QCA and measure the inflated balloon diameter.    -   15. Deflate balloon by pulling negative pressure. While        withdrawing the system, observe tactually and fluoroscopically.        Record any resistance.    -   16. Administer nitroglycerin (200 μg) intra-luminally.    -   17. Assess patency, deployment, and placement of stent via        coronary angiography.    -   18. Assess TIMI angiographic low grade.    -   19. Record on cine and video.    -   20. Measure post-proximal, target, and distal MLD with QCA.    -   21. Repeat Section C with remaining stent delivery systems.    -   22. Measure and record heart rate, arterial blood pressure and        electrocardiogram (ECG).

D. Stent Procedure End

-   -   1. Remove the guidewire, guiding catheter and introducer sheath.    -   2. Remove introducer sheath from the femoral artery.    -   3. Ligate the artery with 3-0 suture material at the side of        sheath entry.    -   4. Appose the muscular and subcutaneous tissue layer using        suture material.    -   5. Allow the animal to recover from anesthesia in an individual        cage.    -   6. Give Buprenorphine (0.05 mg/kg) PRN as needed for pain.    -   7. Administer Ticlopidine (250 mg PO) and aspirin (325 mg PO)        once daily until date of follow-up angiography.

E. Follow-up Angiography for 28-day study pigs

-   -   1. Following an overnight fast, sedate the pigs according to the        institutional standard operating procedure.    -   2. Intubate the trachea via an oral approach.    -   3. Deliver isoflurane at a concentration up to 5% as needed to        maintain surgical plane of anesthesia.    -   4. Shave the cut-down area free of hair and scrub the surgical        site with surgical soap and/or antiseptic solution.    -   5. Measure and record arterial blood pressure, heart rate and        electrocardiogram (ECG).    -   6. Record animal number and study identification tag on cine.    -   7. Advance the guiding catheter over a guidewire to cannulate        the ascending aorta to appropriate vessel.    -   8. Administer nitroglycerine (200 μg IC) prior to angiography.    -   9. Perform an angiogram. Record images on cine and video (if        available).    -   10. Assess patency, deployment and placement of stents via        angiography.    -   11. Obtain online QCA measurements to record the proximal and        distal reference vessel diameters and the minimal luminal        diameters (MLD).    -   12. Give TIMI scores.

F. Procedure End

-   -   1. Remove the guiding catheter and introducer sheath.    -   2. Euthanize the animal with an overdose of barbiturates and/or        potassium chloride.    -   3. Remove the heart and all arteries containing the implanted        stents.    -   4. Perfusion fix the heart and other implanted vessels by        infusing 250 ml of Lactated Ringers solution or physiologic        saline followed by approximately 0.5-1.0 liters of formalin        under a pressure of approximately 100 mmHg.    -   5. Place heart into labeled container with formalin solution for        gross and microscopic examination of heart and implanted        vasculature.    -   6. The percent mean stenosis and percent mean neointimal area        for the different groups were calculated. The following Table 13        demonstrates that both of the formulations of the drug eluting        stents having 40-O-(2-hydroxy)ethyl-rapamycin significantly        reduced the percent stenosis and percent mean neointimal area as        compared to the control groups.

TABLE 13 Percent Percent Mean Treatment Mean Standard NeointimalStandard Group Stenosis Deviation Area Deviation Bare Stent 29.54 14.862.37 1.06 EVOH Control 37.54 10.62 3.00 0.64 Formulation 1 20.67 4.791.64 0.35 Formulation 2 24.29 9.75 1.85 0.38

Example 95

13 mm PIXEL-D stents were coated by spraying a 2% (w/w) solution of EVOHand 98% (w/w) dimethylacetamide. The solvent was removed by baking at140° C. for 2 hours. The target primer layer weight was 58.2 μg. For thereservoir layer, a solution of EVOH and actinomycin D in a mixture of75% (w/w) dimethylacetamide and 25% (w/w) ethanol was spray coated ontothe stents. The ratio of EVOH to actinomycin D was 9 to 1. The stentswere then baked at 50° C. for 2 hours. The target weight for thereservoir layer was 90 μg. A barrier layer was formed by spraying thestents with a solution of EVOH in a mixture of 80% (w/w)dimethylacetamide and 20% (w/w) pentane. Another 2 hour bake at 50° C.was performed to remove the solvent. The target weight for the barrierlayer was 218 μg.

After the solvent had been substantially removed and the coatings hadbeen formed, a select number of stents were then subjected to a standardgrip process in order to mount the stent onto a catheter. The stentswere separated into four test groups. Group 1 served as the controlgroup and were mounted at room temperature; Group 2 was exposed to atemperature of about 82.2° C. (180° F.) for about 2 minutes; Group 3 wasexposed to a temperature of about 93.3° C. (200° F.) for about 2minutes; and Group 4 was exposed to a temperature of about 121.1° C.(250° F.) for about 2 minutes.

Five stents from each group were tested to determine if the totalcontent of the active agent was affected by the thermal treatment. Theresults demonstrated that the thermal treatment process did not affectthe total content. The results for the total drug content test are shownin Table 14.

TABLE 14 Mean Total Standard Content (μg) Deviation (μg) Control 104 3.4Group 1 (82.2° C.) 105 10.1 Group 2 (93.3° C.) 105 7.2 Group 3 (121.1°C.) 107 2.7

Ten stents from each group were then tested to determine the releaserate of the active agent in a 24 hour period. The results demonstratedthat the thermal treatment process decreased the mean release rate for a24 hour period. Additionally, the thermal treatment process decreasedthe standard deviation. The results for the release rate test are shownin Table 15.

TABLE 15 Mean Release Rate Standard (μg/24 hours) Deviation (μg) Control33.1 12.4 Group 1 (82.2° C.) 28.5 7.3 Group 2 (93.3° C.) 19.2 9.6 Group3 (121.1° C.) 21.9 4.0

Example 96

Thirteen (13) mm PIXEL-D stents were coated by spraying a 2% (w/w)solution of EVOH and 98% (w/w) dimethylacetamide. The solvent wasremoved by baking at 140° C. for 2 hours. The target primer layer weightwas 40 μg. For the reservoir layer, a solution of EVOH and actinomycin Din a mixture of 75% (w/w) dimethylacetamide and 25% (w/w) ethanol wasspray coated onto the stents. The ratio of EVOH to actinomycin D was 9to 1, and a target total dose of 7.9 μg. The stents were then baked at50° C. for 2 hours. The target weight for the reservoir layer was 79 μg.A barrier layer was formed by spraying the stents with a solution ofEVOH in a mixture of 80% (w/w) dimethylacetamide and 20% (w/w) pentane.Another 2 hour bake at 50° C. was performed to remove the solvent. Thetarget weight for the barrier layer was 135 μg.

After the solvent had been substantially removed and the coatings hadbeen formed, a select number of stents were then subjected to differentthermal treatment processes. One process included subjecting stents to atwo hour thermal treatment before the mounting process. In particular, aselect number of coated stents were placed in a convection oven andsubjected to a temperature of about 80° C. for about 2 hours. The otherprocess included subjecting stents to a two minute thermal treatmentduring the mounting procedure. In particular, Group 1 was the controlgroup and was mounted at room temperature; Group 2 was exposed to atemperature of about 82.2° C. (180° F.) for about 2 minutes; and Group 3was exposed to a temperature of about 121.1° C. (250° F.) for about 2minutes. Table 16 shows the number of stents used in each of the testgroups.

TABLE 16 Without Two Hour Temperature during Two Hour Thermal ThermalTreatment Stent Mounting Process Treatment Process Process Control (Room10 10 Temperature) Group 1 (82.2° C.) 10 10 Group 2 (121.1° C.) 15 15

Stents from Group 2, including stents from the two hour treatment groupand the non-two hour treatment group, were tested to determine if thetotal content of the active agent was affected by the two hour thermaltreatment process. The results demonstrated that the thermal treatmentprocess did not affect the total content. In particular, the averagetotal content for the stents that were subjected to the two hourtreatment was 9.3 μg/cm²±0.6, whereas the average total content for thestents that were not subjected to the two hour treatment was 8.8μg/cm²±0.6.

A select number of stents from each group were then tested to determinethe release rate of the active agent in a 24 hour period. The resultsdemonstrated that both thermal treatment processes decreased the meanrelease rate for a 24 hour period. The results for the release ratetests are shown in Table 17.

TABLE 17 Mean Release Rate (μg/24 hours) and Standard Deviation WithoutTwo Hour Temperature during Two Hour Thermal Thermal Treatment StentMounting Process Treatment Process Process Control (Room 17.8 ± 4.8 37.0 ± 11.2 Temperature) Group 1 (82.2° C.) 21.2 ± 9.0 28.1 ± 9.0 Group2 (121.1° C.)  9.0 ± 2.7 10.2 ± 1.9

Example 97

13 mm PIXEL-D stents were coated by spraying a 2% (w/w) solution of EVOHand 98% (w/w) dimethylacetamide. The solvent was removed by baking at140° C. for 2 hours. For the reservoir layer, a solution of EVOH andactinomycin D in a mixture of 75% (w/w) dimethylacetamide and 25% (w/w)ethanol was spray coated onto the stents. The ratio of EVOH toactinomycin D was 9 to 1. The stents were then baked at 50° C. for 2hours. A barrier layer was formed by spraying the stents with a solutionof EVOH in a mixture of 80% (w/w) dimethylacetamide and 20% (w/w)pentane. Another 2 hour bake at 50° C. was performed to remove thesolvent.

After the solvent had been substantially removed and the coatings hadbeen formed, the stents were then subjected to various thermal treatmentand storage conditions. In particular, test groups were subjected todifferent conditions to study the effect of (1) exposure temperatures(40° C., 50° C. or 80° C.); (2) exposure time (2 or 7 hours); and (3)storage time (0 or 30 days). Table 18 summarizes the different testparameters.

TABLE 18 Exposure Exposure Time Storage Time at Group Temperature (° C.)(Hours) 25° C. (Days) A0 Room Temperature N/A 0 A1 40 2 0 A2 40 7 0 A350 2 0 A4 50 7 0 A5 80 2 0 A6 80 7 0 B1 50 2 30 B2 50 7 30 B3 80 2 30 B480 7 30

After the stents were exposed to the thermal treatment, the stents weresterilized using an e-beam process. During the e-beam process, thestents were exposed to 35 kGy of radiation using a one pass process.

Five stents from each group were tested to determine if the totalcontent of the active agent was affected by the thermal treatment. Tenstents from each group were then tested to determine the release rate ofthe active agent in a 24 hour period. The results demonstrated that thethermal treatment process did not affect the total content. The resultsalso demonstrated that the thermal treatment process decreased the meanrelease rate for a 24 hour period. The results for the total content andrelease rate test are shown in Table 19.

TABLE 19 Storage Release Exposure Exposure Time at Rate Total ContentTemperature Time 25° C. (%/24 (% of target Group (° C.) (hours) (Days)hours) concentration) A0 Control 16.2 ± 2.0 91.2 ± 1.9 A1 40 2 0 14.9 ±4.6 96.6 ± 5.5 A2 40 7 0 15.0 ± 6.0 83.6 ± 6.9 A3 50 2 0 15.5 ± 3.4 89.2± 8.2 A4 50 7 0 19.3 ± 4.1 87.2 ± 6.1 A5 80 2 0  9.1 ± 2.9  87.7 ± 12.8A6 80 7 0  7.6 ± 1.1 96.9 ± 8.7 B1 50 2 30 20.4 ± 3.0 94.4 ± 8.3 B2 50 730 19.7 ± 4.2 87.6 ± 2.3 B3 80 2 30 11.5 ± 1.8 78.7 ± 8.0 B4 80 7 3010.1 ± 2.2 89.9 ± 3.5

Example 98

DLPLA for this Example was provided by Birmingham Polymers, Inc., 756Tom Martin Drive, Birmingham, Ala. 35211-4467 (Manufacture Lot #DO1O78). According to the manufacture, the DLPLA has an inherentviscosity of 0.55-0.75, a T_(g) of 55° C.-60° C., and lacks a T_(m)(i.e., is amorphous). The viscosity was tested and was determined to be0.67 dL/g in CHCl₃.

Thirteen (13) mm PENTA stents (available from Guidant) were coated byspraying a solution having 1% (w/w) DLPLA, 1% (w/w) everolimus, 78.4%(w/w) 1,1,2-trichloroethane and 19.6% (w/w) chloroform. The apparatusused to coat the stents for this Example and Examples 99-102 was an EFD780S spray device with VALVEMATE 7040 control system (manufactured byEFD Inc., East Providence, R.I.). The solvent was removed by baking atabout 120° C. for about 1 hour. The target drug coating weight afterremoval of the solvent was 300 μg. The stents were then sterilized usingan e-beam process set at 35 KGy.

Example 99

Thirteen (13) mm PENTA stents were coated by spraying a 2% (w/w)solution of DLPLA (0.36 dL/g in CHCl₃), 76.8% (w/w)1,1,2-trichloroethane and 19.2% (w/w) chloroform. The solvent wasremoved and the coating was heat treated by baking at about 120° C. forabout 1 hour. It is estimated that the solvent was removed from thecomposition at this temperature after about 30 minutes of exposure. Thetemperature for the thermal treatment for this Example and for Examples100-102 was selected to be above the T_(m) of any blocks of DPLA or LPLAexisting in the primer polymer. The target primer layer weight afterremoval of the solvent was 100 μg.

For the reservoir layer, a solution of 1% (w/w) DLPLA (0.67 dL/g inCHCl₃, 1% (w/w) everolimus, 76.8% (w/w) 1,1,2-trichloroethane and 19.2%(w/w) chloroform was spray coated onto the stents. The stents were thenbaked at about 50° C. for about 1 hour. The target weight for thereservoir layer after removal of the solvent was 300 μg. The stents werethen sterilized using an e-beam process set at 35 KGy.

Example 100

Thirteen (13) mm PENTA stents were coated by spraying a 2% (w/w)solution of DLPLA (0.36 dL/g in CHCl₃) and 78.4% (w/w)1,1,2-trichloroethane and 19.6% (w/w) chloroform. The solvent wasremoved and the coating was heat treated by baking at about 120° C. forabout 1 hour. The target primer layer weight after removal of thesolvent was 100 μg.

For the reservoir layer, a solution of 1% (w/w) DLPLA (0.67 dL/g inCHCl₃), 1% (w/w) everolimus, 76.8% (w/w) 1,1,2-trichloroethane and 19.2%(w/w) chloroform was spray coated onto the stents. The stents were thenbaked at about 50° C. for about 1 hour. The target weight for thereservoir layer after removal of the solvent was 300 μg.

A barrier layer was formed by spraying the stents with a solution of 2%(w/w) POLYACTIVE in a mixture of 78.4% (w/w) 1,1,2-trichloroethane and19.6% (w/w) chloroform. POLYACTIVE is a trade name of a family ofpoly(ethylene glycol)-block-poly(butyleneterephthalate)-blockpoly(ethylene glycol) copolymers (PEG-PBT-PEG) and is available fromIsoTis Corp. of Holland As indicated by the manufacturer, the grade ofPOLYACTIVE used for this Example and Example 102 had about 45 molar %units derived from PBT and about 55 molar % units derived from PEG. Themolecular weight of the PEG units was indicated to be about 300 Daltons.A 1 hour bake at 50° C. was performed to remove the solvent. The targetweight for the barrier layer after removal of the solvent was 150 μg.The stents were then sterilized using an e-beam process set at 35 KGy.

Example 101

Thirteen (13) mm PENTA stents were coated by spraying a 2% (w/w)solution of DLPLA (0.67 dL/g in CHCl₃) and 78.4% (w/w)1,1,2-trichloroethane and 19.6% (w/w) chloroform. The solvent wasremoved and the coating was heat treated by baking at about 120° C. forabout 1 hour. The target primer layer weight after removal of thesolvent was 100 μg.

For the reservoir layer, a solution of 1% (w/w) DLPLA (0.67 dL/g inCHCl₃), 1% (w/w) everolimus, 76.8% (w/w) 1,1,2-trichloroethane, and19.2% (w/w) chloroform was spray coated onto the stents. The stents werethen baked at about 50° C. for about 1 hour. The target weight for thereservoir layer after removal of the solvent was 300 μg. The stents werethen sterilized using an e-beam process set at 35 KGy.

Example 102

Thirteen (13) mm PENTA stents were coated by spraying a 2% (w/w)solution of DLPLA (0.67 dL/g in CHCl₃) and 78.4% (w/w)1,1,2-trichloroethane and 19.6% (w/w) chloroform. The solvent wasremoved and the coating was heat treated by baking at about 120° C. forabout 1 hour. The target primer layer weight after removal of thesolvent was 100 μg.

For the reservoir layer, a solution of 1% (w/w) DLPLA (0.67 dL/g inCHCl₃), 1% everolimus, 76.8% (w/w) 1,1,2-trichloroethane and 19.2% (w/w)chloroform was spray coated onto the stents. The stents were then bakedat about 50° C. for about 1 hour. The target weight for the reservoirlayer after removal of the solvent was 300 μg.

A barrier layer was formed by spraying the stents with a solution of 2%(w/w) POLYACTIVE in a mixture of 78.4% (w/w) 1,1,2-trichloroethane and19.6% (w/w) chloroform. Another 1 hour bake at 50° C. was performed toremove the solvent. The target weight for the barrier layer afterremoval of the solvent was 150 μg. The stents were then sterilized usingan e-beam process set at 35 KGy.

Example 103

Sample stents from Examples 98-102 were subjected to a wet expansiontest to determine the mechanical integrity of the coatings. Thefollowing procedure was used to determine the mechanical integrity ofthe coatings for each stent.

The stent was mounted on a balloon catheter. The stent and the balloonwere placed in a beaker containing de-ionized water at about 37° C. Todeploy the stent, a pressure of about 8 atm was applied to a balloon forabout 1 minute. The stent-catheter assembly was then taken out from thebeaker, followed by deflating of the balloon and the retraction of thecatheter. After the catheter was refracted, the stent was detached fromthe catheter and dried in air at room temperature for at least eighthours (i.e., over night) before the coating was studied for defects. Thestent coating was observed by using a scanning electron microscope(SEM).

FIGS. 15-19 are SEM photographs of representative stent coatings. FIG.15 provides illustrative results from the stents of Example 98, andshows polymer peeling at the high strain area of the stent structure.FIG. 16 provides illustrative results from the stents of Example 99, andshows a smooth surface with no cracking or other damage at the highstrain area of the stent structure. FIG. 17 provides illustrativeresults from the stents of Example 100, and shows a smooth surface withno cracking or other damage at the high strain area of the stentstructure. FIG. 18 provides illustrative results from the stents ofExample 101, and shows a smooth surface with no cracking or other damageat the high strain area of the stent structure. FIG. 19 providesillustrative results from the stents of Example 102, and shows a smoothsurface with no cracking or other damage at the high strain area of thestent structure.

It was found that the combination of a primer and a thermal treatmentprocess improved the mechanical properties of the stent coatings. Forexample, comparing FIG. 15 with FIGS. 16-19 shows that the thermaltreatment process improve the adhesion of the coatings to the surface ofthe stent.

Example 104

A solution containing DLPLA and acetone was applied to stainless steelstents using a controlled deposition system. After the solution wasapplied, the stents were allowed to dry at room temperature. The targetweight for the coating after removal of the solvent was 200 μg. Thestents were then sterilized using an e-beam process set at 25 KGy.

Example 105

A solution containing everolimus/DLPLA (1:1) was applied to stainlesssteel stents using a controlled deposition system. After the solutionwas applied, the stents were allowed to dry at room temperature. Thetarget weight for the drug coating after removal of the solvent was 400μg. The stents were then sterilized using an e-beam process set at 25KGy.

Example 106

A solution containing DLPLA and acetone was applied to Vision™ stents(available from Guidant) using a spray coating system. After thesolution was applied, the stents were heat treated at 50° C. for 2hours. The target weight for the coating after removal of the solventwas 200 μg. The stents were then sterilized using an e-beam process setat 25 KGy.

Example 107

A solution containing everolimus/DLPLA (1:1) and acetone was applied toVision™ stents using a spray coating system. After the solution wasapplied, the stents were heat treated at 50° C. for 2 hours. The targetweight for the drug coating after removal of the solvent was 400 μg. Thestents were then sterilized using an e-beam process set at 25 KGy.

Example 108

Stents from Examples 104-107 were subjected to dry expanded, wetexpanded or simulated use testing. It was found that the coatings ofExamples 106 and 107 had fewer coating defects than Examples 104 and105. This finding indicates that the thermal treatment of the coatingsimproved the mechanical properties of the coatings.

Example 109

A DSC apparatus was used to study the thermal properties of DLPLApellets and polymeric coatings that included DLPLA. In particular, aMettler-Toledo 822e DSC equipped with an Intracooler (−70° C.) and STAResoftware with ISOStep (modulated DSC) was used for this Example. For theexperiments on polymeric coatings (as disposed on stents), the stentswere flattened longitudinally and folded into a zigzag pattern in orderfor the expanded stents to fit into the DSC pans.

First, the thermal properties of DLPLA pellets were studied using theabove mentioned DSC for two runs. As illustrated in FIG. 20, the pelletsexhibited a T_(g) of about 46° C.

A stainless steel stent was provided (“Stent A”). A coating was formedon a stainless steel stent by applying a DLPLA and acetone solution tothe stent using a controlled deposition system (“Stent B”). The solutionwas allowed to dry at room temperature for 48 to 96 hours.

A coating was formed on another stainless steel stent by applying aneverolimus/DLPLA and acetone solution to the stent using a controlleddeposition system (“Stent C”). The solution was allowed to dry at roomtemperature for 48 to 96 hours.

Stents A, B and C were studied using the above mentioned DSC for tworuns. During the first run, the samples were heated slightly above theT_(g) of the polymeric component to remove the relaxation peak. Theresults from the first run are illustrated in FIG. 21. During the secondrun, as shown illustrated in FIG. 22, the polymeric coatings of bothStent B and Stent C exhibited a T_(g) for the polymer at about 46° C.The T_(m) of the drug was shown to be about 83° C.

A VISION™ stent was provided (“Stent D”). A coating was formed on aVision™ stent to include everolimus/DLPLA (“Stent E”). Stents D and Ewere studied using the above mentioned DSC for two runs. During thefirst run, the samples were heated slightly above the T_(g) of thepolymeric component to remove the relaxation peak. The results from thefirst run are illustrated in FIG. 23. During the second run, as shownillustrated in FIG. 24, the polymeric coating of Stent E exhibited aT_(g) for the polymer at about 36° C. The T_(m) of the drug was shown tobe about 67° C.

While particular embodiments of the present invention have been shownand described, it will be obvious to those skilled in the art thatchanges and modifications can be made without departing from thisinvention in its broader aspects. Therefore, the appended claims are toencompass within their scope all such changes and modifications as fallwithin the true spirit and scope of this invention.

1. A method of manufacturing a stent having a body made at least in partfrom a polymer component, the method comprising exposing the polymercomponent to a temperature equal to or greater than the glass transitiontemperature of the polymer component.
 2. The method of claim 1, whereinthe stent is a biodegradable stent.
 3. The method of claim 1, whereinthe temperature is (a) equal to the glass transition temperature of thepolymer component plus the melting temperature of the polymer component,divided by 2; (b) equal to 0.9 times the melting temperature of thepolymer component, wherein the melting temperature of the polymercomponent is expressed in Kelvin; (c) equal to or greater than thecrystallization temperature of the polymer component; (d) below themelting temperature of the polymer component; or (e) above the meltingtemperature of the polymer component.
 4. The method of claim 1, whereinthe polymer component includes poly(lactic acid).
 5. The method of claim1, wherein the polymer component includes a block copolymer or a graftcopolymer, and wherein a moiety of the block copolymer or the graftcopolymer is poly(lactic acid).
 6. A method of manufacturing animplantable medical device, comprising: forming a first region includinga first polymer on the device; forming a second region of a secondpolymer on the device, the second region including an active agent, thefirst region being over or under the second region; and heating (i) thefirst polymer to a temperature equal to or above the glass transitiontemperature of the first polymer, or (ii) the second polymer to atemperature equal to or above the glass transition temperature of thesecond polymer.
 7. The method of claim 6, wherein the first polymer hasa glass transition temperature greater than the second polymer.
 8. Themethod of claim 6, wherein the second polymer has a glass transitiontemperature greater than the first polymer.
 9. The method of claim 6,wherein the temperature is (a) equal to the glass transition temperatureof the first polymer plus the melting temperature of the first polymercomponent, divided by 2; (b) equal to the glass transition temperatureof the second polymer plus the melting temperature of the second polymercomponent, divided by 2; (c) equal to 0.9 times the melting temperatureof the first polymer or the second polymer, wherein the meltingtemperature is expressed in Kelvin; (d) equal to or greater than thecrystallization temperature of the first or second polymer; (e) belowthe melting temperature of the first or second polymer; or (f) above themelting temperature of the first or second polymer.
 10. The method ofclaim 6, wherein the first or second polymer includes poly(lactic acid).11. The method of claim 6, wherein the first or second polymer includesa block copolymer or a graft copolymer, and wherein a moiety of theblock copolymer or the graft copolymer is poly(lactic acid).
 12. Amethod of manufacturing an implantable medical device, the deviceincluding a polymer and a drug, the method comprising treating thedevice to a temperature greater than ambient temperature for a durationof time, wherein the temperature and the duration of exposure aresufficient to decrease the release rate of the drug from the deviceafter the device has been implanted into a biological lumen.
 13. Themethod of claim 12, wherein the device includes a coating having thepolymer and the drug, the drug being blended in the coating.
 14. Themethod of claim 12, wherein the device is made in whole or in part fromthe polymer.
 15. The method of claim 12, wherein the polymer isbiodegradable.
 16. The method of claim 12, wherein the device is astent.
 17. The method of claim 12, wherein the treatment does not reducethe total content of the drug carried by the device.
 18. The method ofclaim 12, wherein the standard deviation of the mean release rate of thedrug in a 24 hour period is lower than the standard deviation of themean release rate for a group of devices which have not been exposed tothe temperature.
 19. The method of claim 12, wherein the drug israpamycin, 40-O-(2-hydroxy)ethyl-rapamycin, or a functional analog orstructural derivative thereof.
 20. The method of claim 12, wherein thedrug is paclitaxel or docetaxel.
 21. The method of claim 12, wherein thepolymer includes poly(lactic acid).
 22. The method of claim 12, whereinthe polymer includes a block copolymer or a graft copolymer, and whereina moiety of the block copolymer or the graft copolymer is poly(lacticacid).